Fall in Diffusing Capacity Associated With Induction Therapy for Lung Cancer: A Predictor of Postoperative Complication?

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1 SURGERY: The Annals of Thoracic Surgery CME Program is located online at To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal. Fall in Diffusing Capacity Associated With Induction Therapy for Lung Cancer: A Predictor of Postoperative Complication? Shin-ichi Takeda MD, PhD, Yasunobu Funakoshi, MD, PhD, Yoshihisa Kadota, MD, PhD, Masaru Koma, MD, PhD, Hajime Maeda, MD, PhD, Satoko Kawamura, MD, and Yoko Matsubara, MD Departments of General Thoracic Surgery and Anesthesiology, Toneyama National Hospital, Toyonaka City, Osaka, Japan Background. Pulmonary resection after induction therapy is associated with high rates of pulmonary morbidity and mortality. However, the impact of induction therapy on the pulmonary toxicity and associated pulmonary complications has not been fully investigated in the setting of lung cancer surgery. Methods. We assessed the 66 consecutive patients who underwent a pulmonary resection after induction therapy, 48 of whom received chemoradiotherapy and 18, chemotherapy alone. Results of pulmonary function before and after induction therapy were compared, and logistic regression analyses utilized to explore the risk factors of pulmonary morbidity. Results. After induction therapy, forced expiratory volume in 1 second (FEV 1 ) was increased significantly (from L to L; p < 0.05); however, percent vital capacity (%VC) and FEV 1 /FVC did not change significantly. The diffusing capacity of lung for carbon monoxide (DLCO) was decreased significantly by 21% (from 90.3% 18.3% to 71.1% 12.5%; p < ). Patients with respiratory complication showed lower predicted postoperative %FEV 1 (49.5% 11.1% versus 57.2% 14.2%; p 0.031) and predicted postoperative %DLCO (41.9% 8.0% versus 55.4% 10.1%; p < ) results than those without complications. Univariate and multivariate analyses revealed that predicted postoperative %DLCO alone was an independent factor to predict postoperative pulmonary morbidity. Conclusions. For patients who undergo a pulmonary resection after induction therapy, predicted postoperative %DLCO is more important to predict pulmonary morbidity rather than static pulmonary function (predicted postoperative %VC or %FEV 1 ). The decrease in DLCO is thought to reflect a limited gas exchange reserve, caused by the potential toxicity of chemotherapy or chemoradiotherapy. We believe that the impact of diffusion limitation after induction therapy should to be emphasized to decrease the pulmonary morbidity. (Ann Thorac Surg 2006;82:232 6) 2006 by The Society of Thoracic Surgeons Recent applications of induction therapy have expanded the indications of surgery for locally advanced nonsmall-cell lung cancer (NSCLC) and improved postoperative survival. However, induction therapy has also been reported to increase the rates of operative morbidity and mortality [1 4], and a review our institutional experience revealed that the operative morality rate for patients who received a pulmonary resection after induction therapy was 5.5%, whereas it was 0.9% for patients who did not undergo induction therapy [5]. The study also showed that all patients who received induction therapy followed by surgery and then died of adult respiratory distress syndrome/acute lung injury Accepted for publication Jan 10, Address correspondence to Dr Takeda, Toneyama National Hospital, Toneyama 5-1-1, Toyonaka , Japan; stakeda@toneyama. hosp.go.jp. within 30 days had a normal pulmonary function except for a low level of lung diffusion for carbon monoxide (Dlco) [5]. Recently diverse experimental and clinical studies have shown that Dlco represents functional gas exchange capacity [6, 7], and can also independently predict the postoperative morbidity and mortality [8]. Further, Leo and colleagues [9] stressed that even though a reduction in Dlco is often subclinical, it can be a sensitive indicator of lung damage caused by chemotherapy and an important parameter for preoperative evaluation. Unlike patients with other malignancies such as breast and esophageal cancers, who may have lung damage due to the chemotherapy or radiation, lung cancer patients would suffer from further functional loss after undergoing a pulmonary resection. In the present study, we retrospectively reviewed our patient records to determine whether induction therapy 2006 by The Society of Thoracic Surgeons /06/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg TAKEDA ET AL 2006;82:232 6 DIFFUSING CAPACITY AFTER INDUCTION THERAPY 233 Table 1. Pulmonary Function in 66 Patients Who Underwent Induction Therapy for Lung Cancer, and Compared Findings With Those of 200 Prethoracotomy Patients (Control) Control (n 200) has an effect on pulmonary function including lung volumes and Dlco values. In addition, we examined the relevance of impaired pulmonary function toward pulmonary morbidity. Patients and Methods Induction Therapy (n 66) p Value Male/female 138/62 52/ Age (years) Percent VC (%) FEV 1 (L) FEV 1 /FVC(%) Percent Dlco(%) a b a Dlco was corrected by hemoglobin value as described by Cotes et al [11]. b Statistically significant. Dlco diffusing capacity of lung for carbon monoxide; FEV 1 forced expiratory volume in 1 second; FVC forced vital capacity; VC vital capacity. Over a period of 10 years (1995 to 2005), pulmonary resections were performed for 911 consecutive patients with primary NSCLC at our hospital. Of those, 66 (51 males, 15 females; an average age of 60.0 years) who received induction therapy and were evaluated with full pulmonary function tests were included in the current study. Informed consent of induction therapy and preoperative pulmonary function test was obtained from all patients. The protocols of induction therapy were approved by the Institutional Review Board at our hospital. The histologic subtypes included 42 adenocarcinomas, 21 squamous cell carcinomas, and 3 large cell carcinomas. Clinical staging by the TNM classification [10] was performed as follows: evaluation of M1 disease included results from abdominal computed tomogram (CT), bone scan, brain CT, or magnetic resonance imaging (MRI) examinations as well as laboratory tests. There were 5 patients with c-iib disease (Pancoast type), 50 with c-iiia (n2), and 11 with c-iiib (8 patients with T4, invasion into the mediastinum or great vessels, and 3 patients with N3). In the early era, bulky N2 (c-iiia) were candidates for induction therapy without mediastinoscopy. Recently, we aggressively performed transbronchial needle aspiration cytology or mediastinoscopy, or both, for patients with clinical N2 disease before induction therapy. Forty-eight patients received chemoradiotherapy, and 18 underwent chemotherapy alone. Induction chemoradiotherapy consisted of more than two cycles of cisplatin/ vindesine/mitomycin-c or cisplatin/vindesine for 39 patients, and cisplatin/vinorelbine for 9 patients, with conventional radiation therapy applied with an average radiation of 42.5 Gy. Induction chemotherapy consisted of two cycles of cisplatin/vinorelbine for 4 patients, cisplatin/docetaxel for 4, and carboplatin/docetaxel for 10. The operative procedures included 46 lobectomies, 4 bilobectomies (including 8 sleeve resection), and 16 pneumonectomies, which included 63 R0 (no microscopically residual tumor) and 3 R1 (no gross residual tumors) resections. Two hundred consecutive lung cancer patients who underwent a pulmonary resection without induction therapy within the same period (1999 to 2001) were chosen and used as the control group to compare the pulmonary function values. The pulmonary function test and Dlco before and after induction therapy were determined in 32 patients, while those measurements were performed only after induction therapy (preoperation) in the other 34 patients. Spirometry was performed using a System 9 (Minato Medical Science, Osaka, Japan), and Dlco was measured by a single breath method and corrected with the hemoglobin value as reported by Cotes and associates [11]. Postoperative predictive pulmonary function including predicted postoperative percent vital capacity (ppo%vc), predicted postoperative percent FEV 1 (ppo%fev 1 ), and predicted postoperative percent Dlco (ppo%dlco) were estimated using lobar functional contribution as we previously reported [12], and a split function was applied using terchnetium-99mlabeled macroaggregates of albumin (99mTc-MAA) in case for pneumonectomy cases [13, 14]. The preinduction and postinduction therapy pulmonary function results were compared. To determine the predictors of postoperative morbidity, several factors including demographics, radiotherapy, preoperative and predictive pulmonary functional values were analyzed using logistic analysis. Postoperative pulmonary complications included pneumonia based on chest radiographic findings that required antibiotics, hypoxemia, atelectasis requiring repeated bronchofiberscopy, respiratory failure requiring reintubation with mechanical ventilation, and bronchopleural fistula, empyema, and severe chylothorax requiring reoperation. All other complication such as prolonged air leak, atrial fibrillation, and heart failure were not included in the analysis. Hospital mortality included 30-day mortality and operation-related deaths during the same hospitalization. Data are reported as the mean SD or as a proportion. Comparisons of pulmonary function measurements taken at preinduction and postinduction therapy were Table 2. Pulmonary Function Before and After Induction Therapy in 32 Patients Before After p Value Percent VC (%) FEV 1 (L) a FEV 1 /FVC(%) Percent Dlco(%) a a Statistically significant. Dlco diffusing capacity of lung for carbon monoxide; FEV 1 forced expiratory volume in 1 second; FVC forced vital capacity; VC vital capacity.

3 234 TAKEDA ET AL Ann Thorac Surg DIFFUSING CAPACITY AFTER INDUCTION THERAPY 2006;82:232 6 Table 3. Pulmonary Function and Complications in Patients Who Underwent Induction Therapy for Lung Cancer No Complications Complication (Death) p Value Number (5) Male/female 36/8 15/7 (4/1) Age (years) ( ) Percent VC (%) ( ) ppo%vc (%) ( ) FEV 1 (L) ( ) ppo%fev 1 (%) ( ) b FEV 1 /FVC(%) ( ) Percent Dlco(%) a ( ) b ppo%dlco(%) a ( ) b a Hemoglobin-adjusted Dlco. b Statistically significant. Dlco diffusing capacity of lung for carbon monoxide; FEV 1 forced expiratory volume in 1 second; FVC forced vital capacity; ppo predicted postoperative; VC vital capacity. performed using Student s paired t test. Comparisons were made using unpaired and 2 tests. To identify pulmonary function values, as well as clinical and demographic variables associated with pulmonary morbidity and mortality, stratified logistic regression analyses were subjected to explore the risk factors. Variables significantly related to the morbidity (p 0.1) in univariate analyses were considered in a multivariate analysis. Significance was accepted as a p value of less than 0.05 (StatView 5.0; Abacus Concepts, Berkeley, California). Results There were no significant differences in sex distribution, age, %VC, FEV 1, and FEV 1 /FVC values between the patients who underwent induction therapy and control group. In contrast, Dlco was lower in the induction therapy patients (p ) (Table 1). Further, an increase in FEV 1 was found after induction therapy (from L to L; p 0.05), however, and %VC and FEV 1 /FVC did not change significantly (Table 2). After being corrected by the hemoglobin value, Dlco was decreased significantly by 21% after induction therapy (from 90.3% 18.3% to71.1% 12.5%; p ). Operation-related deaths occurred in 5 patients (7.6%) including 2 with 30-day mortality (3.0%) due to adult respiratory distress syndrome and acute pulmonary embolism, and 3 late hospital deaths (empyema in 2 patients and respiratory failure in 1). Twenty-nine patients had postoperative complications (44.0%), and 22 patients (33.3%) experienced postoperative respiratory complications, which included 9 with pneumonia, 5 with respiratory failure requiring mechanical ventilation, 4, with atelectasis, 3 with empyema, and 3 with long-standing hypoxemia. Comparisons of predicted postoperative pulmonary function values between patients without complications (uncomplicated group, n 44) and those with complications (complication group, n 22) revealed no significant differences for sex distribution, age, preoperative %VC, ppo%vc, FEV 1, and FEV 1 /FVC (Table 2). In contrast, the complications group showed a lower ppo% FEV 1 (49.5% 11.1% versus 57.2% 14.2%; p 0.031), and significant differences were found for %Dlco (62.6% 9.7% versus 74.4% 11.5%; p ).and ppo%dlco (41.9% 8.0% versus 55.4% 10.1%; p ) (Table 3). Univariate and multivariate analyses (Table 4) revealed that ppo%dlco was a strong independent factor to predict postoperative pulmonary morbidity followed by ppo%vc (p ) and ppo%fev 1 (p ). In addition, ppo%dlco was the only independent factor able to predict pulmonary morbidity by multivariate analysis, while there were no predictors of postoperative mortality using similar analysis. Comment Induction therapy has shed a light for locally advanced NSCLC in terms of rendering them the tumors to be resectable [4, 15, 16]. However, a neutropenia and renal dysfunction as well as related susceptibility to infection have been reported in regards to patient eligibility in the setting of induction therapy [3, 15, 16]. In the present study, we focused on the change of lung volumes and diffusing capacity, and their relevance to pulmonary morbidity. In general, induction chemotherapy or chemoradiotherapy has favorable effects toward FEV 1 by ameliorating bronchial obstruction caused by tumor extension [17, 18], which was observed in the current patients. However, radiotherapy induced pulmonary toxicity toward Dlco has been reported [2, 4, 17 19] as well as that induced by the chemotherapeutic agents including bleomycin [19], mitomycin-c [20], gemcitabine [21], and cisplatin [21, 22]. Previous reports of high-dose chemotherapy for the treatment of nonseminomatous germ cell tumors showed that a 40% to 50% decrease in Dlco in patients who received high-dose chemotherapy [22 24], with operative deaths due to acute interstitial pneumonia or adult respiratory distress syndrome [24, 25]. In the current study, we did not clarify or compare the toxicity of each chemotherapeutic agent or the additive effects of radiation therapy. Nevertheless, our results showing a 14% to 20% decrease in Dlco by postoperative chemo-

4 Ann Thorac Surg TAKEDA ET AL 2006;82:232 6 DIFFUSING CAPACITY AFTER INDUCTION THERAPY 235 Table 4. Univariate Analysis of Factors Influencing the Pulmonary Morbidity and Mortality in 66 Patients After Induction Therapy Using Stepwise Logistic Regression Analysis Variable Subset Percent of PM RR (95% CI) p Value Age (years) 60 (n 38) ( ) (n 28) 35.7 Sex Male (n 51) ( ) Female (n 15) 33.3 Histology Sq La (n 24) ( ) Adenocarcinoma (n 42) 31.0 C stage T4 (n 11) ( ) T1 3 (n 55) 34.5 P stage IIIA, IIIB (n 20) ( ) I, II (n 46) 30.4 Radiation Yes (n 48) ( ) No (n 18) 27.8 Extended Yes (n 33) ( ) No (n 33) 30.3 ppo%vc (%) 70 (n 25) ( ) (n 41) 29.3 ppo%fev 1 (%) 50 (n 27) ( ) (n 39) 25.6 FEV 1 /FVC (%) 60 (n 15) ( ) (n 51) 31.4 ppo%dlco(%) a 40 (n 16) ( ) a 40 (n 50) 20 a Statistically significant. CI confidence interval; Dlco diffusing capacity of lung for carbon monoxide; FEV 1 forced expiratory volume in 1 second; FVC forced vital capacity; La large cell; PM pulmonary morbidity; RR relative risk; Sq squamous; VC vital capacity. therapy with carboplatin and paclitaxel (unpublished data) support the effects of chemotherapy alone. In addition to the effects of induction therapy and its pulmonary toxicity, further functional loss in the lung cancer patients due to a pulmonary resection is an important issue. Our finding thus clearly demonstrated the impact of chemotherapy and chemoradiotherapy on diffusing capacity and its relevance with respiratory complications after lung resections. In this sense, preoperative Dlco and ppo%dlco values were more important than lung volumes such as VC and FEV 1. Thus, the importance of diffusing limitation [8] was confirmed in the setting of induction therapy for NSCLC. Dissociation of lung volume and Dlco should not be overlooked when planning a lung resection for patients after induction therapy, particularly for those patients with marginal pulmonary functional reserve. It is known that diffusing capacity is composed of membranediffusing capacity (Dmco) and pulmonary capillary volume (Vc) [6, 7], and that Dlco increases with reference to the cardiac output. However, few studies have shown the effects of chemotherapeutic agents on Dmco and Vc, although bleomycin was found to decrease both components, while etoposide affected Dmco alone [25]. In our analysis of postoperative complications in patients who underwent induction therapy, major respiratory complications including radiation pneumonia, adult respiratory distress syndrome, and prolonged oxygen supplementation were frequently encountered. One explanation could be that those were associated with a decrease in Dlco as well as limited pulmonary vascular and lymphatic system reserves, which may have been due to pneumonitis induced by radiation or chemotherapy. The exclusive goal of induction therapy should be

5 236 TAKEDA ET AL Ann Thorac Surg DIFFUSING CAPACITY AFTER INDUCTION THERAPY 2006;82:232 6 exclusively aimed at complete surgical resection aiming at curing disease. Therefore, patients with marginal pulmonary function require additional functional evaluation in the light of their high-risk condition [4, 5]. Regarding such functional evaluation, we recently examined a method of exercise oxygen desaturation that represented diffusing limitation over the cardiac output [6, 8, 26, 27], with maximal oxygen uptake reflecting patient performance [13, 26] as an additional factor for making a final decision for lung resection candidates. Another aspect to consider regarding induction therapy is remote function after a lung resection. Previously, we analyzed the late pulmonary function in patients 1 year after undergoing a lobectomy, and found that that induction chemoradiotherapy alone was the factor that affected a postoperative decrease in VC and FEV 1 [28]. Those results in addition to the findings in current series reveal that a lung resection after induction therapy causes additional pulmonary function loss also in the late phase. Surgeons and anesthesiologists should consider the impact of induction therapy and impaired pulmonary function that occurs during the perioperative period. Further, low %Dlco strongly indicates subclinical lung damage and ppo%dlco can be used to predict the functional volume of gas exchange capacity [6 8]. The risks of surgery must be carefully balanced and individualized with a better chance for survival in locally advanced NSCLC patients requiring induction therapy as well as restaging after induction therapy to select the survival benefited patients and to avoid surgery for nonresponders. 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