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Eur J Cardiothorac Surg 2006;29:896-901
© 2006 Elsevier Science NL

Postoperative complications after induction chemoradiotherapy in patients with non-small-cell lung cancer

Shiro Fujita a , b , * , Nobuyuki Katakami b , Yutaka Takahashi c , Keiko Hirokawa d , Akihiko Ikeda b , Chiharu Tabata a , Tadashi Mio a , Michiaki Mishima a

a Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Syogoin Kawaracho, Sakyo-ku, Kyoto 606-8507, Japan
b Division of Respiratory Medicine, Kobe City General Hospital, 4-6 Minatojima-nakamachi, Chuo-ku, Kobe 650-0046, Japan
c Division of Thoracic and Cardiovascular Surgery, Kobe City General Hospital, 4-6 Minatojima-nakamachi, Chuo-ku, Kobe 650-0046, Japan
d Division of Radiology, Kobe City General Hospital, 4-6 Minatojima-nakamachi, Chuo-ku, Kobe 650-0046, Japan

Received 20 January 2006; received in revised form 6 March 2006; accepted 13 March 2006.

* Corresponding author. Address: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Syogoin Kawaracho, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: +81 75 751 3830; fax: +81 75 751 4643. (Email: sfujita{at}kuhp.kyoto-u.ac.jp).


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Objective: This study evaluates the risks of postoperative complications in 124 patients with non-small-cell lung cancer who received pre-operative induction chemoradiotherapy and surgery. Methods: All patients with non-small-cell lung cancer who underwent surgery after induction therapy between January 1990 and December 2003 were reviewed. We adopted univariate and multiple logistic regression models to identify predictors that increased the incidence of postoperative complications. Results: Of 124 patients, 59 received carboplatin and docetaxel, 53 received cisplatin and etoposide, and 12 received other platinum-based combinations. Pre-operative thoracic radiotherapy was performed concurrently with chemotherapy. The median dose to the primary tumor was 40 Gy, and 29 patients (23.4%) received radiotherapy of more than 45 Gy before surgery. There were 25 pneumonectomies (20.2%). The overall postoperative mortality was 9 of 124 patients (7.3%), and complications developed in 54 patients (43.5%). Multivariate analysis demonstrated that only thoracic radiotherapy of more than 45 Gy predicted postoperative complications (P = 0.021; odds ratio, 3.620; 95% confidence interval, 1.214–10.797). Conclusions: Thoracic radiotherapy of more than 45 Gy, in combination with chemotherapy, was a significant risk factor for postoperative complications.

Key Words: Induction therapy • Non-small-cell lung cancer • Postoperative complications • Radiotherapy • Surgery


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
Surgical resection is still the best curative therapy for non-small-cell lung cancer (NSCLC); however, surgery alone is not adequate for most cases, considering a 5-year survival rate of less than 15% in stage IIIA-N2 disease and approximately 50% in T2N0 disease [1]. The theoretical advantages of pre-operative induction therapy lie in a potential increase in the resectability rate and a lower rate of distant relapse owing to eradication of micrometastases, both of which may contribute to achieving long-term survival for these patients. After encouraging results of several clinical trials for patients in stage IIIA-N2 disease [2,3], the concept of induction therapy followed by surgical resection found general acceptance and is now being adopted in patients with earlier stages of the disease.

The optimal induction regimen remains to be determined. To date, the results of many large trials indicate that pathological downstaging, particularly mediastinal nodes, is the most important predictor for long-term survival [4–7]. Radiotherapy in combination with chemotherapy before surgery seems to be beneficial in this context, because a better response rate is estimated as compared with chemotherapy alone, and this advantage has been shown in some studies [8,9].

However, taking the possible increase of morbidity and mortality into account, induction therapy should always be done cautiously. Of all treatment-related adverse events, most seem to be observed during the postoperative period [4], and precise information about the risks of these events is extremely important but few consistent findings are available. In the present study, we performed a retrospective analysis of patients with NSCLC who received induction chemoradiotherapy before surgery at our institution. We used univariate and multiple logistic regression models to identify risk factors that increased the incidence of postoperative complications.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
Between January 1990 and December 2003 all patients with NSCLC who underwent surgery after induction chemoradiotherapy at Kobe City General Hospital, Kobe, Japan were reviewed retrospectively. Informed consent was obtained and this study was approved by the local Ethical Committee. Data collected included demographic information, pulmonary function tests, electrocardiograms and pretreatment clinical stage. Pretreatment evaluation for staging consisted of a computed tomographic (CT) scan of the chest and abdomen, a brain CT scan or magnetic resonance imaging, and a radionuclide bone scan. A positron emission tomographic scan was conducted recently. With respect to the N factor, especially mediastinal nodes, a pathological evaluation (e.g. mediastinoscopy) was recommended but not performed routinely due to bulky nodes or patient's refusal. Details about the medical co-morbidities (hypertension, ischemic heart disease, cardiac dysfunction, arrhythmia, cerebrovascular diseases, diabetes and diseases requiring daily systemic corticosteroid therapy), induction therapy and surgical procedure were collected.

Pulmonary resection was performed in an attempt to achieve complete resection of the tumor. Lymphadenectomy usually included interlobar, hilar and ipsilateral lymph nodes. Extended resection was defined as a procedure that included combined resection of surrounding structures and a complex lobectomy with reconstruction of bronchus. The bronchial stump was closed by hand-suturing in all patients. From 1995, we started to reinforce the bronchial stump with viable tissue, but the decision to do this was at the discretion of the operating surgeon.

Postoperative complications were defined as postoperative adverse events that caused a prolonged length stay in hospital: pneumonia, delayed postoperative extubation for more than 48 h, bronchopleural fistula, acute lung injury/acute respiratory distress syndrome (ALI/ARDS), empyema, bleeding episode or wound infection requiring surgical intervention, vocal cord palsy, atelectasis requiring bronchoscopy, chylothorax, prolonged air leak for more than 7 days, arrhythmia requiring treatment, myocardial infarction, heart failure, renal failure requiring dialysis, sepsis, cerebrovascular accident and pulmonary embolism were considered as complications. Postoperative mortality included death up to 90 days after operation or during the same stay in hospital. Thirty-day mortality was not used in this study, because it usually underestimates actual postoperative mortality [10,11].

The effects of risk factors were first evaluated with univariate analysis. Categorical variables were analyzed by Fisher's exact test or the {chi} 2 test. Continuous variables were assessed with unpaired t-tests or the Mann–Whitney U-test. Variables were selected for further analysis if their probability values were less than 0.10 by univariate analysis. In order to avoid problems of multi-colinearity, correlation among predictor variables was analyzed first and then multiple logistic regression analysis was performed. Because of the small number of deaths, no statistical analysis of mortality was conducted. All tests were two-tailed and probability values of 0.05 or less were considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
3.1 Patient characteristics
Between 1990 and 2003, a total of 124 consecutive patients underwent surgery after induction chemoradiotherapy for NSCLC. The characteristics of the patients are shown in Table 1 . Sixty-six patients had an adenocarcinoma, 49 patients had a squamous cell carcinoma and 9 patients had an unspecified NSCLC. Commonly recorded medical co-morbidities were hypertension (20.2%), diabetes (12.9%) and ischemic heart disease (4.0%). Pulmonary function tests were conducted before induction therapy. Diffusing capacity was measured only in those patients with poor pulmonary function.


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  		Table 1. Patient characteristics (n = 124)
 
3.2 Pre-operative therapy
Multimodality treatment of induction chemoradiotherapy followed by surgery was started from 1990 at our institute. With respect to chemotherapy regimens, 59 patients were treated with pre-operative chemotherapy consisting of two courses of carboplatin AUC 5 on day 1 and docetaxel 60 mg/m2 on day 1, 53 patients with two courses of cisplatin 20 mg/m2 on days 1–5 and etoposide 40 mg/m2 on days 1–5, and the remaining 12 patients with other platinum-based combinations. The period between the last chemotherapy and resection was 4 weeks.

Radiation treatment planning for all patients was based on CT scans. Conventional two-dimensional radiotherapy was performed during the period. The target volume included the primary lesion, ipsilateral hilar lymph nodes and mediastinum, with a 1.0–2.0 cm margin. All treatment was delivered in daily fractions of 2.0 Gy concurrently with the chemotherapy described above. The cumulative median dose to the primary tumor was 40 Gy (range 27–68 Gy). Twenty-nine patients (23.4%) received thoracic radiotherapy of more than 45 Gy before surgery.

During the study period, two phase II studies and one phase III study were conducted. From 1994, one phase II study of induction chemoradiotherapy (two courses of cisplatin 20 mg/m2 on days 1–5 and etoposide 40 mg/m2 on days 1–5, in combination with 40 Gy radiotherapy to the primary tumor and mediastinal nodes) was conducted and 22 patients were enrolled. In the course of one phase II study and one phase III study, 43 patients were treated with pre-operative concurrent chemoradiotherapy (two courses of carboplatin AUC 5 on day 1 and docetaxel 60 mg/m2 on day 1, with 40 Gy radiotherapy). The remaining patients were treated with various chemoradiotherapy regimens. In general, at the beginning of the study period, relatively high-dosage radiotherapy (50–60 Gy) was delivered with chemotherapy. The total dose of pre-operative radiotherapy tended to be reduced gradually from 1994 in response to several reports indicating the risks of high-dosage radiotherapy [12]. From 2000, the conservative radiotherapy (30–45 Gy) in combination with platinum-based chemotherapy was always adopted as the pre-operative induction regimen at the institute.

3.3 Surgery
There were 25 pneumonectomies, 90 lobectomies, 7 bilobectomies and 1 segmentectomy. One patient had an exploration only. Twenty-two patients had a left-sided pneumonectomy and 3 a right-sided pneumonectomy. A R0 surgical resection was achieved in 116 patients (93.5%); a R1 resection was achieved in 3 patients (2.4%) and a R2 resection in 4 patients (3.2%). Thirty-five patients (28.2%) had extended resections, including the pericardium in 22 patients, the chest wall in 8 patients, the parietal pleura in 3 patients, the major vessels in 2 patients and the diaphragm in 1 patient. No patient underwent complex resection with bronchoplasty. Resection and reconstruction of the pulmonary artery was performed in 5 patients.

Bronchial stump reinforcement was performed in 36 patients (29.0%), with intercostal muscle flap (n = 35) or greater omentum (n = 1). The median intraoperative blood loss was 387 mL (range 54–3453 mL); 68 patients (54.8%) were transfused with a median of 4.0 (±4.2) units. The operative time ranged from 80 to 525 min (median 235 min).

3.4 Distribution of variables and incidence of adverse events
Before statistical analysis, the relationship between continuous variables and incidence of adverse events was assessed. As shown in Fig. 1 , as pre-operative radiation dosage increased, the incidence of morbidity rose in proportion, but in a rather imbalanced way. A steep increase of incidence was found around a dosage of 45 Gy (Fig. 1). This finding suggested that the pre-operative radiation dosage should be categorized with a cut-off point of 45 Gy. We chose a dosage of 45 Gy as the cut-off point and categorized the patients into two groups for further analysis. A similar imbalanced increase could not be observed with respect to age, a forced expiratory volume in 1 s (FEV1), FEV1 (percentage of predicted), the amount of intraoperative blood loss and the length of the operation.


Figure 1
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  		Fig. 1. Relationships between the incidence of adverse events and the total dose of thoracic pre-operative radiotherapy.

 
3.5 Complications
Fifty-four patients (43.5%) presented at least one postoperative complication. Common complications are listed in Table 2 . The most common complications were prolonged air leak, arrhythmia and bronchopleural fistula. As for prolonged air leak, observation or pleurodesis was adequate for cure. No patient underwent re-thoracotomy for this adverse event. In the vast majority of patients (n = 23), prolonged air leak was the only postoperative complication. Postoperative air leak tended to persist in patients who received thoracic radiotherapy with more than 45 Gy (P = 0.001). Bronchopleural fistula occurred in 5 patients, in 2 of them after pneumonectomy (2 on the right side and 3 on the left side), which resulted in fatal outcome in 4 patients. Two of the 5 patients received pre-operative thoracic radiotherapy with more than 45 Gy. Bronchopleural fistula occurred in 1 of 36 patients with the bronchial stump protected.


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  		Table 2. Common complications
 
Univariate analysis showed that male gender, old age, low serum albumin, FEV1 (percentage of predicted), thoracic radiotherapy with more than 45 Gy, extended resection, increased blood loss, the length of the operation and earlier date of surgery (during 1990–1996) were associated significantly with postoperative complications (Table 3 ). The correlation between these factors was analyzed first. FEV1 (percentage of predicted) was correlated to male gender with statistical significance (P < 0.009). Blood loss was correlated significantly to extended resection, the length of the operation and earlier date of surgery (P < 0.001, each). A multiple logistic regression analysis revealed that only pre-operative thoracic radiotherapy with more than 45 Gy was a significant predictor of postoperative morbidity (Table 4 ).


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  		Table 3. Factors affecting postoperative complications
 

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  		Table 4. Multivariate analysis of factors predicting complications
 
3.6 Mortality
The overall postoperative mortality was 7.3% (n = 9). The 30-day mortality was 2.4% and the late surgical mortality (>30 days postoperatively) was 4.9%. The causes of death were sepsis due to bronchopleural fistula (n = 4), cardiac failure (n = 2), ARDS (n = 1), empyema without bronchopleural fistula (n = 1) and cytomegalovirus pneumonia (n = 1).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
The reported incidence of postoperative morbidity and mortality after induction therapy varies in different studies, probably due to the sample size, the regimens of pre-operative treatment, the experience of the medical staff involved and definitions of postoperative complications [13]. Previous studies have reported that the rate of postoperative morbidity ranged from 40 to 60%, and mortality ranged from 4 to 20% [8,10,12–15]. The morbidity of 43.5% and mortality of 7.3% in our series are very similar to the findings in those reports.

Pre-operative thoracic radiotherapy of more than 45 Gy proved to be a significant risk factor for postoperative complications in the present study. The association between higher-dosage radiotherapy administered pre-operatively and postoperative complications was first mentioned by Fowler and co-workers [12]. Thirteen patients underwent resection after concurrent thoracic radiotherapy with 60 Gy in daily 2 Gy fractions with cisplatin, etoposide and 5-fluorouracil; excessive rates of morbidity (62%; 8 of 13 patients) and mortality (23%; 3 of 13 patients) were recorded. The authors concluded that the high-dosage pre-operative radiotherapy may adversely influence patients in the postoperative state. They noted also that the high-dosage radiotherapy may increase the incidence of two life-threatening complications, bronchopleural fistula and culture-negative diffuse pulmonary infiltrate (the clinical and radiological characteristics of these conditions were similar to, if not identical with, those of acute lung injury or acute respiratory distress syndrome). After this report, several large multi-institutional trials of induction chemoradiotherapy followed by surgery were conducted [5,6,8,16]. The total dose of thoracic radiation was limited to 30–45 Gy in most of these trials, because of concern for unacceptable rates of postoperative morbidity and mortality after relatively high-dosage radiotherapy. In fact, pre-operative radiotherapy, limited to 45 Gy with concurrent chemotherapy, was proved to be safe and feasible in these trials; however, this limitation was based mostly on the authors’ experience. The results of our study support this conservative thoracic radiotherapy in a pre-operative setting with statistical significance.

The mortality profile associated with pre-operative relatively high-dosage thoracic radiotherapy could not be evaluated in our study because of the small number of deaths. However, bronchopleural fistula, ALI and ARDS, all of which are considered to be more frequent after high-dosage thoracic radiotherapy, were recorded [12]. Bronchopleural fistula was observed in five patients (4.0%) and was the leading cause of mortality (n = 4). Many investigators have shown that thoracic radiation is one of the important risk factors for bronchopleural fistula [8,16,17]. Ischemia in the bronchial mucosa around the area of the resected bronchus is considered to play a central role in the etiology of this complication [18,19]. All patients in this series received pre-operative radiotherapy, and some patients (23.4%) received high doses of greater than 45 Gy. Pre-operative radiation, high-dosage in particular, seems to be one of the main causes of postoperative mortality in the current study. Besides radiation, proper surgical techniques are important for bronchial stump healing. We could not demonstrate a preventive effect of bronchial stump reinforcement against bronchopleural fistula because the number of patients with this complication (n = 5) was too small to provide any consistent results. Several reports have noted that bronchial stump reinforcement with a viable tissue, such as an intercostal muscle, can reduce the risk of bronchopleural fistula [15,16,20]. Sonett and co-workers [20] reported safe and feasible pulmonary resections in 40 patients, even after curative-intent radiotherapy (more than 59 Gy) and concurrent chemotherapy, with bronchial stump reinforcement done almost routinely. We reinforced the bronchial stump according to individual evaluation during the study, but routine stump reinforcement may be an effective and advisable procedure for prevention of bronchial stump complications, especially if the dosage of pre-operative radiation is relatively high. With respect to ALI/ARDS, probably because the rate of pneumonectomy was low (20.2%) and intensive work-up was always done to rule out diseases mimicking primary postoperative ALI/ARDS (e.g. infectious pneumonia), the incidence (2.4%) was almost equal to that of the reports of pulmonary resection without induction chemoradiotherapy [21,22].

In contrast to most previous reports, in which cardiac dysrhythmias were the leading postoperative complication, prolonged air leak was much more prevalent than other events in our series. All patients were cured without thoracotomy, indicating that the etiology of the air leak was disruption of lung parenchyma, not bronchial insufficiency. A number of authors have described the relationship between pre-operative radiotherapy and prolonged air leak [15,23]. Thoracic radiotherapy induces tissue damage of the lung parenchyma, resulting in slow re-expansion of the remaining lung. Persistent pleural space may cause several types of complication, one of which is prolonged air leak. Radiation-induced fibrosis and scarring cause surgical techniques to become more complex. Adhesion, commonly encountered in irradiated structures, can cause injury in the visceral pleura during surgical manipulation. The results of our study showed that only a radiation dosage of more than 45 Gy was a significant predictor of postoperative complications (P = 0.021), and that it was related to the prolongation of air leaks (P = 0.001). In the etiology of classic radiation pneumonitis, it is generally accepted that there is a threshold dose level above which the incidence of the disease increases [24]. A similar threshold dose level may exist for pre-operative radiotherapy, which, when exceeded, causes prolongation of air leak after pulmonary resection.

A significant increase in the rate of complications was not found after pneumonectomy. Several reports have described the risks for pneumonectomy [4,10,25], but various authors have emphasized the risk of right-sided pneumonectomy [7,13]. Martin and co-workers [13] reported an excess mortality of 23.9% and a significantly increased risk of morbidity (P = 0.020) for right-sided pneumonectomy in their retrospective analysis. Of 25 patients who underwent pneumonectomy, the number of right-sided pneumonectomies was very small (n = 3), which may provide an explanation for the small impact on the incidence of postoperative complications in our series.

Limitations to our study include the retrospective design of the analysis, the length of the study and the mode of radiotherapy administration. This was a single-institution retrospective analysis of patients with locally advanced NSCLC, not a prospective trial. The induction regimens were not uniform because patients were treated over a period of 14 years. Conventional two-dimensional radiotherapy was administered in the present study. In many institutions, however, two-dimensional radiotherapy has been replaced gradually by three-dimensional conformal radiotherapy, which can reduce toxicity to nearby cancer-free tissues.

It may be concluded that induction chemoradiotherapy that includes thoracic radiation with a dosage of more than 45 Gy significantly increases postoperative complications after thoracotomy for NSCLC. The most common complication was prolonged air leak, and physicians should be aware of the devastating complication, bronchopleural fistula, which was the leading cause of death in the postoperative period. The benefit of pre-operative high-dosage thoracic radiotherapy must be weighed against these risks.


   Acknowledgments
 
We thank Dr Satoshi Teramukai and Dr Masatsugu Nakagawa for their important advice on the statistical analysis.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

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