Abstract

OBJECTIVES

To assess the complication rate in participants of the screen arm of the NELSON lung cancer screening trial who underwent surgical resection and to investigate, based on a literature review, whether the complication rate, length of hospital stay, re-thoracotomy and mortality rates after a surgical procedure were different from those of the non-screening series, taking co-morbidity into account.

METHODS

Between April 2004 and December 2008, 198 subjects underwent thoracic surgery. Co-morbid conditions were retrieved from the medical records. Postoperative complications were classified as minor and major.

RESULTS

In total, 182 thoracotomies, 5 thoracotomies after video-assisted thoracoscopic surgery (VATS) and 11 VATS procedures were performed. In these patients, 36% had chronic obstructive lung disease, 16% coronary artery disease, 14% diabetes mellitus and 11% peripheral vascular disease. Following thoracotomy, 47% (88/187) had ≥1 minor (7–57% in literature) and 10% (18/187) ≥1 major complication (2–26% in literature); following VATS, 38% (6/16) had ≥1 minor complication, but no major complications. Seventeen per cent (3/18) of major complications and 21% (20/96) of minor complications were seen in subjects operated for benign disease. The re-thoracotomy rate was 3% and there was no 30-day mortality after thoracotomy or VATS (0–8.3% in literature). The mortality rate of 0% after surgical procedures is low when compared with the non-screening series (0–8.3%); the rate of complications (53%) is within range when compared with the non-screening series (8.5–58%).

CONCLUSIONS

In conclusion, mortality rates after surgical procedures are lower in the NELSON lung cancer screening trial than those in the non-screening series. The rate of complications is within the same range as in the non-screening series.

Trial registration number: ISR CTN 63545820.

INTRODUCTION

It has been shown that lung cancer screening by low-dose multi-detector computer tomography (CT) can detect lung cancer in a high proportion at an early stage [1]. Before considering implementation of CT screening, a reduction in lung cancer mortality has to be demonstrated by randomized clinical trials and the balance between the benefits and harms of screening has to be evaluated thoroughly. Important aspects to be taken into account are the effect of CT screening on health-related quality of life, and the occurrence of complications associated with the work-up and treatment of participants with a positive test result. Patient-related factors, such as a poor general health status, age and co-morbidity, contribute to the risk of postoperative pulmonary complications [2]. Screening populations usually consist of heavy current and former smokers at an advanced age and at high risk for co-morbid disease. In several studies, it has been shown that co-morbidity can predict morbidity and mortality of surgical procedures [3]. To be able to make a fair comparison with the mortality and complication data reported in non-lung cancer screening series, the co-morbidity of the screen population has to be assessed. Our objective was to assess the complication rate in participants in the screen arm of the Dutch-Belgian lung cancer screening trial (NELSON) who underwent a surgical resection and to investigate, based on a literature review, whether the complication rate, length of stay and re-thoracotomy and mortality rates after a surgical procedure were different from those of the non-screening series.

PATIENTS AND METHODS

Inclusion criteria and work-up

NELSON trial participants were current and former smokers at high risk for lung cancer. Detailed information on the inclusion and exclusion criteria have been reported before [4]. Current and former smokers aged 50–75 with a smoking history of >15 cigarettes/day during >25 years or >10 cigarettes/day during >30 years (quit ≤10 years ago) were invited. Subjects with a moderate or bad self-reported health unable to climb two flights of stairs and persons with a body weight ≥140 kg were excluded, as were those with a history of other cancers. The prospective screening study was approved by the Ministry of Health and by the Medical Ethical Boards of each of the four participating hospitals. Written informed consent was obtained from all participants. In the NELSON trial, 7557 subjects underwent a CT scan at baseline, the second screening round (1 year after baseline) and the third screening round (2 years after the second round) [1]. Subjects with a positive test result were referred for work-up to a pulmonologist and, depending on the outcome of this work-up, a resection of the suspicious lesion was performed. The standard non-invasive work-up included a physical exam, pulmonary function test, bronchoscopy, FDG-PET-scan and a standard-dose CT scan with intravenous contrast of the chest and upper abdomen.

CT data acquisition and image reading

Data acquisition and image reading were as described before [5]. In brief, all four participating screening sites used 16-detector CT scanners (Sensation-16, Siemens Medical Solutions, Forchheim, Germany Mx8000 IDT or Brilliance 16P, Philips Medical Systems, Cleveland, OH, USA). Scan data were obtained in a spiral mode, with 16 × 0.75 mm collimation and 1.5 pitch. No contrast was administered. Data acquisition and scanning conditions were standardized and equal for baseline and repeat screening. Digital workstations (Leonardo®, Siemens Medical Solutions, Erlangen, Germany) were used in all screening sites with commercially available software for semi-automated volume measurements (LungCare®, Siemens Medical Solutions, version Somaris/5: VA70C-W).

Nodule management and diagnostic work-up

At baseline, a scan was considered positive if any non-calcified nodule had a solid component >500 mm3 (>9.8 mm in diameter) and indeterminate whether the volume of the largest solid nodule or the solid component of a partially solid nodule was 50–500 mm3 (4.6–9.8 mm in diameter) or >8 mm in diameter for non-solid nodules [5]. Subjects with an indeterminate result had a follow-up scan 3 months later to assess growth. Significant growth was defined as a change in volume between the first and second scan of ≥25%. Subjects with positive screening tests were referred to a chest physician for work-up and diagnosis [1]. If lung cancer was diagnosed, the participant was treated for the disease and went off screening; if no lung cancer was found the regular second-round CT scan was scheduled 12 months after the baseline scan. For participants with one or more new nodules on the second-round scan, the result (positive or negative) was based on the size of the nodule, as for round one; in the case of an indeterminate result, a follow-up scan was performed 6 weeks later [5]. For participants with previously existing nodules, the second-round result was based on the volume doubling time (VDT). If there was no growth, or if the VDT was >600 days, the scan was declared negative [1]. If the VDT was <400 days, or if a new solid component had emerged in a previously non-solid nodule, the scan was considered to be positive. When the VDT was 400–600 days, the test was indeterminate and a follow-up scan was done 1 year after the second round. With a VDT of <400 days, the final result was considered to be positive. If both new and existing nodules were present, the nodule with the largest volume or fastest growth determined the result. All participants with a negative second-round result were invited to undergo the third screening ∼2 years after the second round. Work-up and staging were standardized for all screening sites according to national and international guidelines and included a physical exam, a standard CT scan with contrast of the chest and upper abdomen, FDG-PET scan and a bronchoscopy [5]. Subjects with a negative non-surgical work-up were referred for surgery to obtain histology of the suspicious nodule. Bronchoscopies were done in accordance with Dutch national guidelines in order to evaluate the central airways and (if possible) to diagnose lung cancer or benign disease. Pulmonologists and thoracic surgeons were not blinded to the PET result. All subjects with suspected lung cancer were discussed in multidisciplinary tumour boards, which included a thoracic surgeon, before progressing to surgery; all imaging studies were available during these meetings. National and international pathology review panels evaluated all cytological and histological specimens.

Operative details

All resections were performed at one of the four screening centres, of which three were academic institutions and one a peripheral hospital. In Groningen three experienced thoracic surgeons were involved, in Haarlem two, in Louvain three and in Utrecht eleven. Participants with a benign diagnosis after non-surgical work-up were scheduled for the next screening round. In the remaining test-positive subjects, the suspicious nodules were removed either by VATS or thoracotomy with wedge resection and frozen section. A preoperative tissue biopsy was not routine. Lobectomies were performed only for central nodules that could not be approached by wedge resection, meaning limited resections were performed for benign lesions. If lung cancer was diagnosed by VATS, the procedure was converted to an open thoracotomy with sampling of the lobar, interlobar, hilar and mediastinal lymph nodes; this is because VATS resection for lung cancer was not yet fully implemented in daily practice in the Netherlands at the time of the present study. A mediastinoscopy was performed before proceeding to VATS or thoracotomy in subjects with mediastinal lymph nodes larger than 10 mm in the short-axis and/or FDG-PET positive mediastinal lymph nodes. No specific strategies were employed to prevent prolonged air leak, such as reinforced staple lines. The chest tube was removed if there was no air leak and the fluid production was 200 ml or less per 24 h.

Data collection and co-morbidity scoring

The date, nature, number and outcome of all adverse events related to all diagnostic and treatment procedures between April 2004 and 31 December 2008 were entered into an electronic web-based database—the NELSON Management System—by investigators at the four screening sites after completion of the diagnostic work-up and therapeutic procedures. In addition, a hard copy of the medical records of all subjects referred for work-up and treatment was centrally stored at the data centre of Erasmus MC Rotterdam in order to review for complications. Co-morbid conditions were retrieved from the medical records based on the medical history at the time of referral because of a positive test result. Subjects were defined as having chronic obstructive pulmonary disease (COPD) when the forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) ratio was <0.70 and/or the medical history mentioned COPD and the participant used inhaled steroids and/or bronchodilators. Coronary artery disease included a history of myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty or angina pectoris. Peripheral vascular disease included a history of intermittent claudication, abdominal aneurysm, percutaneous transluminal angioplasty or bypass grafting of the peripheral arteries.

Literature search

A review of the literature was performed using a Pubmed search up to February 2011. The search string consisted of a combination of medical subject headings [MeSH] and keywords including ‘Lung Neoplasms’, ‘Postoperative Complications’, ‘Co-morbidity’, ‘Mortality’, ‘Thoracotomy’, ‘Thoracic Surgery, Video-Assisted’ and related synonyms. We summarized the main results of the literature study and the current study with regard to co-morbidity and adverse events following thoracotomy in forest plots. This was not done for VATS procedures in view of the low number of VATS procedures in the current study. Lack or incomplete reporting of co-morbidity was not used as an exclusion criterion. Studies in which all participants had previously received chemotherapy and/or radiotherapy were excluded. For studies without classification of complications, complications were scored according to our definitions of minor and major complications, provided that a complete overview of all complications was reported. In addition, in the case of studies that graded complications based on the Common Terminology Criteria for Adverse Events, grade 4–5 events were considered major complications.

Definitions of complications

Postoperative mortality was defined as death within 30 days after the operation or within the same hospital admission. According to EuroSCORE [6] and Birim et al. [7], major complications included bleeding requiring re-operation, empyema, pneumonia (Center for Disease Control and Prevention definition of nosocomial pneumonia [2]) myocardial infarction, renal failure requiring temporary or permanent dialysis, postoperative stroke, critical arrhythmia (ventricular fibrillation, ventricular tachycardia) and pulmonary embolism. Additional major complications included respiratory failure requiring ventilator support for >48 h [8] and postoperative heart failure with pulmonary oedema [9]. We classified a chylothorax, haemothorax and gastro-intestinal complications requiring operative re-intervention (re-thoracotomy) or laparotomy as major complications. Non-life threatening complications were classified as minor complications. All minor and major complications were scored for each VATS and thoracotomy procedure.

Statistical analysis

Data were analysed using SPSS (version 17.0, SPSS, Inc., Chicago, IL, USA). A two-tailed Mann–Whitney U-test was used to analyse continuous data in the absence of normal distribution. The Chi-squared (χ²) test was used for binomial or categorical data and Fisher's exact test for small groups. Statistical significance was defined as a P-value <0.05. Asymmetric confidence intervals (CI) were calculated for the literature study data presented in Figs. 1 and 2 using log-linear regression, where we estimated the observation as the log of a β; a weighted standard error (SE) was calculated for this β and subsequently the CI was obtained.

Figure 1:

Prevalence of chronic obstructive pulmonary disease, coronary artery disease, diabetes mellitus and peripheral vascular disease in NELSON lung cancer screening participants who underwent a thoracotomy in comparison with non-screening series from the literature.

Figure 1:

Prevalence of chronic obstructive pulmonary disease, coronary artery disease, diabetes mellitus and peripheral vascular disease in NELSON lung cancer screening participants who underwent a thoracotomy in comparison with non-screening series from the literature.

Figure 2:

Complication and mortality rates after thoracotomy in the NELSON lung cancer screening trial in comparison with non-screening series from the literature.

Figure 2:

Complication and mortality rates after thoracotomy in the NELSON lung cancer screening trial in comparison with non-screening series from the literature.

RESULTS

Background and treatment characteristics

A total of 415 subjects had a positive test result following CT screening between April 2004 and December 2008. The role of FDG-PET in the work-up of these test-positive participants has been described elsewhere. In 17 of the participants surgical procedures consisted of a mediastinoscopy only; 15 were subsequently diagnosed with lung cancer, which was at an early stage in 2, who were inoperable because of co-morbidity (Fig. 3). In 178 participants, the final benign diagnosis was based on FDG-PET, CT with intravenous contrast or biopsies. Transthoracic biopsies were only performed in 5% (22/415) of test-positive participants. In 22 participants the diagnosis was cancer; subjects did not undergo resection because of advanced stage disease (13 subjects) or co-morbidity (9 subjects), the latter group being treated with stereotactic radiotherapy. In these 22 subjects, the diagnosis was based on biopsies in 15 cases and on imaging studies in 7 cases. In 198 participants, non-surgical work-up showed lung cancer or was inconclusive. These subjects underwent a resection either by thoracotomy (n = 182), VATS converted to thoracotomy (n = 5) or wedge resection by VATS (n = 11) (Fig. 3). The characteristics of the subjects who underwent a resection are presented in Tables 1 and 2. The most frequent co-morbid conditions were COPD (36%), coronary artery disease (16%), diabetes mellitus (14%) and peripheral vascular disease (11%) (Table 2). Table 1 shows the clinical and pathological lung cancer stages. Three subjects with clinical stage III (T4N0M0) were operated and a microscopic complete resection could be achieved. Five subjects had pathological stage IV lung cancer after surgery. Two of them had an indeterminate preoperative FDG-PET result, which in retrospect appeared to be metastatic lesions. In two patients the preoperative FDG-PET was false-negative for distant metastasis. In one subject, no preoperative FDG-PET was made due to an administrative error; the postoperative FDG-PET scan showed distant metastasis. Of eight patients with pathological stage III disease, this was due to unforeseen N2 disease in seven patients and due to a bronchoalveolar carcinoma in the middle lobe, which was resected in one patient; a second suspicious upper lobe nodule could not be found during surgery. The clinical stage at that time was cT1N0M1. One month later the upper lobe nodule showed rapid growth and mediastinal lymphadenopathy was noted (clinical stage T1N2M0); mediastinoscopy showed metastasis of a large cell carcinoma.

Figure 3:

Surgical procedures and outcome in 415 screen positives of the NELSON randomized lung cancer screening trial.

Figure 3:

Surgical procedures and outcome in 415 screen positives of the NELSON randomized lung cancer screening trial.

Table 1:

Characteristics of the participants of the NELSON lung cancer screening trial who underwent a thoracotomy and/or video-assisted thoracoscopic surgery (VATS) after a positive screening test

Characteristics Lung surgery (n = 198) 
Age (range) 61 (50–74) 
Female (%) 35 (18) 
Pack years (range) 46 (21–133) 
COPD (%) 71 (36) 
GOLD I FEV1 ≥80% 38 (19) 
GOLD II 50% ≤FEV1 <80% 20 (10) 
GOLD III 30% ≤FEV1 <50% 6 (3) 
Stage unknown (%) 7 (4) 
Type of resection (%) 
 Lobectomy or bilobectomy 137 (70) 
 True cut biopsy, segment or wedge resection 56 (26) 
 Pneumonectomy 4 (2) 
 Sternotomy 1 (0.5) 
 Lung cancer (%) 139 (70) 
 Benign disease (%) 47 (24) 
 Other cancer (%) 12 (6) 
Clinical lung cancer stagea (%) 
 I 117 (84) 
 II 18 (13) 
 III (3 T4N0M) 3 (2) 
 IV (1 T1N0M0) 1 (1) 
Pathological lung cancer stage (%) 
 I 112 (81) 
 II 11 (8) 
 III (4 T1N2M0; 2 T2N2M0; 2 T4N1M0; 1 T4N0M0; 2 T3N2M0) 11 (8) 
 IV 5 (4)  
Characteristics Lung surgery (n = 198) 
Age (range) 61 (50–74) 
Female (%) 35 (18) 
Pack years (range) 46 (21–133) 
COPD (%) 71 (36) 
GOLD I FEV1 ≥80% 38 (19) 
GOLD II 50% ≤FEV1 <80% 20 (10) 
GOLD III 30% ≤FEV1 <50% 6 (3) 
Stage unknown (%) 7 (4) 
Type of resection (%) 
 Lobectomy or bilobectomy 137 (70) 
 True cut biopsy, segment or wedge resection 56 (26) 
 Pneumonectomy 4 (2) 
 Sternotomy 1 (0.5) 
 Lung cancer (%) 139 (70) 
 Benign disease (%) 47 (24) 
 Other cancer (%) 12 (6) 
Clinical lung cancer stagea (%) 
 I 117 (84) 
 II 18 (13) 
 III (3 T4N0M) 3 (2) 
 IV (1 T1N0M0) 1 (1) 
Pathological lung cancer stage (%) 
 I 112 (81) 
 II 11 (8) 
 III (4 T1N2M0; 2 T2N2M0; 2 T4N1M0; 1 T4N0M0; 2 T3N2M0) 11 (8) 
 IV 5 (4)  

COPD: chronic obstructive pulmonary disease; GOLD: global initiative for chronic obstructive lung disease.

aSixth edition of TNM lung cancer classification.

Table 2:

Co-morbidity in NELSON participants who underwent a thoracotomy and/or video-assisted thoracoscopic surgery (VATS)

Co-morbidity Lung surgery (n = 198) (%) 
Chronic obstructive pulmonary disease 71 (36) 
Coronary artery disease 31 (16) 
Diabetes mellitus 28 (14) 
Peripheral vascular disease 22 (11) 
Peptic ulcer disease 7 (4) 
Cerebrovascular disease 5 (3) 
Congestive heart failure 5 (3) 
Connective tissue disease 4 (2) 
Any prior tumour 16 (8) 
Chronic kidney disease 2 (1) 
Co-morbidity Lung surgery (n = 198) (%) 
Chronic obstructive pulmonary disease 71 (36) 
Coronary artery disease 31 (16) 
Diabetes mellitus 28 (14) 
Peripheral vascular disease 22 (11) 
Peptic ulcer disease 7 (4) 
Cerebrovascular disease 5 (3) 
Congestive heart failure 5 (3) 
Connective tissue disease 4 (2) 
Any prior tumour 16 (8) 
Chronic kidney disease 2 (1) 

Complications after surgery

Tables 3 and 4 present all the complications observed. Following thoracotomy, 47% (88/187) had at least one minor and 10% (18/187) at least one major complication. Thirty-eight per cent (6/16) of the VATS procedures was complicated by at least one minor complication, but no major complications have been observed. As 5% had both minor and major complications, the proportion of participants with any complication was 53%. Seventeen per cent (3/18) of major complications and 21% (20/96) of minor complications were seen in subjects operated for benign disease. The overall median length of hospital stay was 13 days (2–51 days) after thoracotomy and 8 days (4–12 days) after VATS. In subjects with minor complications, this was 15 days (6–51 days) and 9 days (7–12 days), respectively. In the case of major complications following thoracotomy, the median length of stay was 21 days (range 8–51 days). The re-thoracotomy rate was 3% after thoracotomy and 0% after VATS. Re-admissions occurred in 5% of those who underwent a thoracotomy (eight after minor complications and one after a major complication), but were absent after VATS. There was no 30-day mortality after the thoracotomies or VATS procedures in NELSON. Table 5 shows that a higher rate of minor complications was seen in the case of more extensive resections. Limited resections (true-cut biopsies, and wedge and segment resections) were associated with a lower rate of minor complications (OR: 0.51, 95% confidence interval 0.26–1.03, P-value 0.06) when compared with bilobectomy/lobectomy and pneumonectomy. No significant correlation could be established for type of resection and risk of major complications. Five subjects were re-admitted because of minor complications: in three subjects with chest pain and one with dyspnoea a pulmonary embolism could be excluded; in one subject with pleuritic effusion an empyema was excluded; no repeat chest tube placement or thoracentesis was necessary (Table 3). Atelectasis was diagnosed by chest X-ray in nine subjects, on five of whom bronchoscopy was performed.

Table 3:

Overview of all minor complications following 187 thoracotomies and 16 video-assisted thoracoscopic surgery (VATS) procedures performed in the NELSON trial

Minor complication Thoracotomy (%) VATS (%) 
Air-leakage more than >5 days 42 (23) 5 (31) 
Supraventricular tachycardia 17 (9) 
Infection 16 (9) 1 (6) 
Diaphragm paralysis 10 (5) 
Chest tube more than >5 days due to persistent pleural fluid 8 (4) 
Atelectasis 8 (4) 1 (6) 
Drop hand 3 (2) 
Wound infection 3 (2) 
Delirium 3 (2) 
Chest pain 3 (2) 
COPD exacerbation 2 (2) 2 (13) 
Blood transfusion 2 (2) 
Urinary retention 2 (2) 
Haemoptysis 2 (2) 
Persistant ptosis 1 (1) 
Paralysis serratus anterior muscle 1 (1) 
Deep venous thrombosis 1 (1) 
Ileus 1 (1) 
Pleuritic effusion 1 (1) 
Dyspnoea 1 (1) 
Minor complication Thoracotomy (%) VATS (%) 
Air-leakage more than >5 days 42 (23) 5 (31) 
Supraventricular tachycardia 17 (9) 
Infection 16 (9) 1 (6) 
Diaphragm paralysis 10 (5) 
Chest tube more than >5 days due to persistent pleural fluid 8 (4) 
Atelectasis 8 (4) 1 (6) 
Drop hand 3 (2) 
Wound infection 3 (2) 
Delirium 3 (2) 
Chest pain 3 (2) 
COPD exacerbation 2 (2) 2 (13) 
Blood transfusion 2 (2) 
Urinary retention 2 (2) 
Haemoptysis 2 (2) 
Persistant ptosis 1 (1) 
Paralysis serratus anterior muscle 1 (1) 
Deep venous thrombosis 1 (1) 
Ileus 1 (1) 
Pleuritic effusion 1 (1) 
Dyspnoea 1 (1) 

COPD: chronic obstructive pulmonary disease; VATS: video-assisted thoracoscopic surgery.

Table 4:

Overview of the major complications following thoracotomy in 187 participants of the NELSON trial

Major complications n (%) 
Pneumonia 10 (5) 
Empyema 2 (1) 
Bleeding, re-operation 1 (1) 
Chylothorax, re-operation 1 (1) 
Pulmonary embolism 1 (1) 
Respiratory failure 1 (1) 
Myocardial infarction 1 (1) 
Congestive heart failure 1 (1) 
Ventricular tachycardia 1 (1) 
Bowel perforation 1 (1) 
Major complications n (%) 
Pneumonia 10 (5) 
Empyema 2 (1) 
Bleeding, re-operation 1 (1) 
Chylothorax, re-operation 1 (1) 
Pulmonary embolism 1 (1) 
Respiratory failure 1 (1) 
Myocardial infarction 1 (1) 
Congestive heart failure 1 (1) 
Ventricular tachycardia 1 (1) 
Bowel perforation 1 (1) 
Table 5:

Complications according to type of resection

Surgical procedures
 
Minor complications following thoracotomy
 
Major complications following thoracotomy
 
Surgical procedure Minor complications following VATS
 
Type of surgery n (%) Any (%)a Total Any (%)a Total N (%) Any (%)a Total 
True-cut biopsy 6 (3) 2 (33)       
Wedge resection 35 (19) 11 (31) 14 3 (9) 16 (100) 6 (38) 
Segmentectomy 4 (2) 1 (25) 1 (25)       
Lobectomy 131 (70) 40 26 69 (53) 101 11 13 (10) 15       
Bilobectomy 5 (3) 4 (80) 1 (20)       
Sleeve resection 1 (1)       
Pneumonectomy right 1 (1) 1 (100)       
Pneumonectomy left 3 (2)       
Sternotomy 1 (1)       
Total 187 (100) 53 31 88 (47) 127 16 18 (10) 20 16 (100) 6 (38) 
Surgical procedures
 
Minor complications following thoracotomy
 
Major complications following thoracotomy
 
Surgical procedure Minor complications following VATS
 
Type of surgery n (%) Any (%)a Total Any (%)a Total N (%) Any (%)a Total 
True-cut biopsy 6 (3) 2 (33)       
Wedge resection 35 (19) 11 (31) 14 3 (9) 16 (100) 6 (38) 
Segmentectomy 4 (2) 1 (25) 1 (25)       
Lobectomy 131 (70) 40 26 69 (53) 101 11 13 (10) 15       
Bilobectomy 5 (3) 4 (80) 1 (20)       
Sleeve resection 1 (1)       
Pneumonectomy right 1 (1) 1 (100)       
Pneumonectomy left 3 (2)       
Sternotomy 1 (1)       
Total 187 (100) 53 31 88 (47) 127 16 18 (10) 20 16 (100) 6 (38) 

aPercentage of type of surgery.

Data from the literature review

Our literature search revealed 16 studies on thoracotomy and 12 studies on both thoracotomy and VATS which met our selection criteria (Supplementary Table S1). The prevalence of co-morbidity in the literature on thoracotomy ranged between 43 and 80% ([3, 7], Supplementary Table S1A). Figure 1 shows the prevalence of co-morbidities in subjects who underwent a thoracotomy in non-lung cancer screening studies. The most frequently reported co-morbid conditions were COPD (10–52%), coronary artery disease (10–52%), diabetes mellitus (7–19%) and peripheral vascular disease (6–26%). The number of lobectomies performed during thoracotomy procedures varied between 40 and 100% [22] (Suemitsu, 2009), while pneumonectomies were done in 0–27% [10, 14] (Pagni, 1998). The median percentage of stage I disease in the thoracotomy group was 69.0% (range: 31–100%) [10, 11]. The mortality rates reported after a thoracotomy varied between 0 and 8% (Fig. 2). The National Emphysema Treatment Trial (NETT) found a 90-day mortality of 5% following lung volume reduction surgery in subjects with severe emphysema (mean FEV1 0.7 l (26% of that predicted)) [12]. Figure 2 shows that major and minor complications after thoracotomy varied in the ranges of 4–26% and 7–57%, respectively. The median length of stay after a thoracotomy reported in the literature was 5–22 days [13] (Boffa, 2008). The reported re-thoracotomy rates after a thoracotomy varied between 0 and 9% [7, 13].

In the majority of the studies on VATS, lobectomies were performed. Complications after VATS were reported in 9–51% (Kim, 2010; Petersen, 2010) and major complications in only 0–12% [17] (Jaklitsch, 1996; Petersen, 2010). The median length of stay after a VATS reported in the literature was 4–23 days [13] (Villamizar, 2009). The reported re-operation rate after a VATS varied between 1 and 5% [13] (Paul, 2010), with a mortality rate of 0–4% [21] (Handy, 2009).

DISCUSSION

Our study compared the complications rates, length of hospital stay, re-thoracotomy and mortality rates of participants in the NELSON trial who underwent thoracic surgery with data from non-screening series. The comparison with non-screening series could be made because we demonstrated that the age range and co-morbidity level of the NELSON trial participants who underwent a surgical resection was the same as those in the non-screening series.

Literature review and complications

The studies included in our literature review displayed a large heterogeneity with respect to the definition, classification and way in which data on complications have been collected so far. For example, prolonged air leak has been defined as >5 days [7] and >7 days [13]. In addition, chest-tube management with regard to output differs in studies or is not defined. Few authors make a distinction between minor and major complications, and complication data are collected by reviewing individual patient charts, based on ICD-9 codes [14] or on claims in Medicare files [3]. The latter methods may lead to under-reporting of complications, especially for minor complications. Probably because we screened all individual patient files, our minor complication rates are in the higher range of what has been reported before. The most important observation was the relatively low rate of major complications and the absence of postoperative mortality after the thoracotomy and VATS procedures performed in the screen arm of the NELSON trial. This could probably be explained by the fact that screening participants are normally asymptomatic individuals, that screen-detected tumours are usually smaller [15, 16] and that a pneumonectomy was required less often in the NELSON compared with the literature, where more complex resections with a higher expected complication rate were performed. Nevertheless, the proportion of stage I disease was in the same range of what has been reported in our literature review of the non-screening series.

Lung cancer-screening studies and complications

In a recent study, Infante et al. [17] report on the outcome of surgical procedures in the DANTE trial. A total of 59 subjects underwent a thoracotomy procedure. Three died following the thoracotomy and a total of 20 complications were noted, which were major complications in nine subjects. No major complications or postoperative deaths were seen in subjects diagnosed with benign disease. Fifteen subjects underwent a VATS procedure; no postoperative deaths or major complications were noted in this subset of patients. The postoperative mortality rate in the DANTE study was higher than expected; all subjects had central tumours of stage IIA or higher, two had co-morbid conditions and two had undergone a pneumonectomy. Veronesi et al. [18] reported that 25% of subjects developed complications following thoracotomy and VATS procedures, which were serious in 6% and required re-operation in 2%. No postoperative complications or mortality was noted in the subjects with benign disease. While only two subjects underwent a pneumonectomy in their study [18], pneumonectomies were performed on four subjects in our study. Infante et al. [17] performed a relatively high number of pneumonectomies, in seven subjects in total, which may explain the higher mortality rate. The rate of major complications in lung cancer screening studies is at the lower limit when compared with that in the literature. Mortality rates are also at the lower limit [18]; however, with more extensive resections the rate may be the same as in the literature [17]. An important observation to make is that no major complications and no deaths were seen in subjects operated for benign disease [17, 18]. In our study, however, 17% (3/18) of major complications and 21% (20/96) of minor complications were seen in subjects operated for benign disease.

Length of stay after VATS and thoracotomy

Despite these observations, the length of stay (LOS) after thoracotomy and VATS procedures was not shorter for NELSON participants than the average. This can be explained by the fact that patients in the Netherlands and Belgium usually stay in the surgery or pulmonary medicine department and do not routinely go to a short-stay facility after surgery. It has been shown that LOS decreases when the use of skilled nursing facilities increases [19]. Another possible explanation may be that in the Netherlands and Belgium it is socially much less accepted to discharge patients home after three or four days. None of the participants in the NELSON study went to a long-term nursing facility. Prolonged air leak has been described as the most important factor for prolonged hospital stay [20]; this was not the case in the current study, presumably because of less severe emphysema.

Type of resection

In the NELSON trial, VATS procedures were only performed for wedge resections, whereas in the majority of studies VATS was used to perform lobectomies, which is a major difference. This is due to the fact that VATS lobectomy had only recently been introduced in the Netherlands at the time of the study [21]. The proportion of lobectomies in the thoracotomy group was comparable with the literature. Therefore, and because of the low number of VATS procedures in the current study, the comparison we made between the VATS results in the NELSON screening trial and the non-screening series from the literature should be interpreted with caution. There is general consensus in the literature that morbidity and mortality rates after VATS are lower than after thoracotomy, and that patients have a better postoperative physical functioning and a shorter postoperative length of stay [22]. In addition, the oncological validity of VATS resections for lung cancer has been proved as 5-year survival rates are similar to those after thoracotomy [23]. We therefore believe that lung cancer screening sites should be equipped to perform VATS procedures, especially in view of the substantial risk of false-positive test results and resections for benign disease [1].

SUMMARY

In the NELSON lung cancer screening trial, the rate of minor complications after thoracotomy and VATS was in the upper range of what has been reported for the non-screening series, while the rate of major complications was in the lower range. The postoperative length of stay was not shorter than in the literature. The re-thoracotomy rate for complications such as a haemothorax requiring re-intervention was in the same range in NELSON as that reported in the literature, but no re-thoracotomies were performed after VATS. No postoperative deaths were observed after the thoracotomy and VATS procedures. To our knowledge, this is the first report on the prevalence of co-morbidity and of complications in a lung cancer screening population. Veronesi et al. [18] presented data on complications in abstract form in their lung cancer screening study, but without information on co-morbidity. Their results support our encouraging data, which demonstrate that participants are at low risk of major complications or postoperative death following thoracotomy or VATS lung cancer screening. However, the high rate of resection for benign disease and associated morbidity continues to be a concern. Seventeen per cent of the major complications and 21% of the minor complications were seen in subjects operated for benign disease. The use of FDG-PET [24] and combination of FDG-PET and VDT [25] may help to reduce the number of resections for benign disease. In conclusion, mortality rates after surgical procedures were lower in the NELSON lung cancer screening trial than in the non-screening series. The rate of minor and major complications is within the same range as in the non-screening series.

SUPPLEMENTARY MATERIAL

Supplementary material is available at EJCTS online.

Funding

The NELSON trial is financially supported by Zorg Onderzoek Nederland-Medische Wetenschappen (ZonMw), KWF Kankerbestrijding, Stichting Centraal Fonds Reserves van Voormalig Vrijwillige Ziekenfondsverzekeringen (RvvZ), G. Ph. Verhagen Foundation, Rotterdam Oncologic Thoracic Study Group (ROTS), Erasmus Trust Fund, Stichting tegen Kanker (Belgium), Vlaamse Liga tegen Kanker and LOGO Leuven and Hageland. We thank Siemens Germany for providing four digital workstations and Roche Diagnostics for an unrestricted research grant. We also wish to thank Tom and Josephine De Rijke for their legacy gift.

Conflict of interest: none declared.

ACKNOWLEDGEMENTS

We thank the surgeons at the four screening sites who performed the surgeries on participants in the NELSON study. Groningen: D.J. Drenth, T.J. Klinkenberg and Y.N. Drijver; Haarlem: H. Rijna and H.L.F. Brom. Louvain: G. Decker and E. Internullo and Utrecht: J. Kluin, P.F.A. Bakker-de Wekker, R.C.A. Meijer and F.Z. Ramjankhan. We thank Harry de Koning (Department of Public Health, Erasmus MC Rotterdam), Matthijs Oudkerk (Department of Radiology, UMC Groningen), Willem Mali (Department of Radiology, UMC Utrecht) and Frederik Thunnissen (Department of Pathology, VUMC Amsterdam) for their critical review of the manuscript and their comments, which have been appreciated. Our thanks to René Vernhout (Department of Pulmonology, Erasmus MC Rotterdam) for developing the database used to register complications and data management support. We thank Roel Faber, ICT manager, for his assistance, and Linda van Dongen for her support in data management; and also the local data managers: Henk Pruiksma (Haarlem), Liesbet Peeters (Louvain), Saskia van Amelsvoort-van de Vorst (Utrecht) and Ria Ziengs (Groningen). Finally, our thanks to Caspar Looman for his assistance with the statistics.

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