Abstract
Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for both the development of primary lung cancer, as well as poor outcome after lung cancer diagnosis and treatment. Because of existing impairments in lung function, patients with COPD often do not meet traditional criteria for tolerance of definitive surgical lung cancer therapy. Emerging information regarding the physiology of lung resection in COPD indicates that postoperative decrements in lung function may be less than anticipated by traditional prediction tools. In patients with COPD, more inclusive consideration for surgical resection with curative intent may be appropriate as limited surgical resections or nonsurgical therapeutic options provide inferior survival. Furthermore, optimizing perioperative COPD medical care according to clinical practice guidelines including smoking cessation can potentially minimize morbidity and improve functional status in this often severely impaired patient population.
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States (1). In addition to the irreversible airflow obstruction that characterizes the disease, COPD is recognized as a systemic inflammatory disorder with numerous additional pulmonary and extrapulmonary manifestations, including an increased risk for development of primary lung cancers (2). The association between COPD and lung cancer has been reported in numerous studies and is notably independent of patient age or extent of tobacco exposure (3, 4). The risk of lung cancer in patients with COPD is two- to fivefold greater compared with smokers without COPD (5–7).
Although the risk of lung cancer in patients with COPD has long been established, progress in surgical care as well as an expanded understanding of the physiology of lung resection in COPD may help improve outcomes for patients with COPD and lung cancer. Central to achieving improved outcomes is greater consideration of surgical resection with curative intent, as limited surgical resections (8–10) or nonsurgical therapeutic options (11–13) provide inferior survival compared with resection. Furthermore, optimization of perioperative medical care, as well as medical care in nonsurgical patients, can potentially minimize morbidity and improve functional status in this severely impaired population.
Chronic inflammation associated with COPD likely plays a role in the pathogenesis of lung cancer, just as chronic inflammation contributes to malignant transformation in other organs (14–16). Inflammation in COPD may result in repeated airway epithelial injury and accompanying high cell turnover rates and propagation of DNA errors resulting in amplification of the carcinogenic effects of cigarette smoke (17). Although all lung cancer cell types occur in the setting of COPD, airflow obstruction has been specifically associated with increased risk for squamous cell carcinoma (6, 18, 19). Some have postulated that impaired mucociliary clearance of carcinogenic substances from cigarette smoke, owing to chronic airflow obstruction, increases exposure of the bronchial epithelium to these carcinogens and promotes pathologic changes leading to squamous cell neoplasia (19). Some of the hypothesized mechanisms of association between COPD and lung cancer are shown in Figure 1.
Figure 1. Hypothesized mechanisms of the association between chronic obstructive pulmonary disease (COPD) and lung cancer.
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Figure 2. This computed tomography scan serves as an illustrative example from the authors' clinical program of early-stage lung cancer in a patient with chronic obstructive pulmonary disease (COPD). This 76-year-old man with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage 2 COPD had an incidentally detected 1.3 × 1.3 cm right upper lobe lung nodule. Preoperative postbronchodilator FEV1 was 1.52 L (52% of predicted), FVC was 3.06 (75% of predicted), FEV1/FVC ratio was 50%, and diffusion capacity to carbon monoxide (DlCO) was 47% of predicted. His preoperative 6-minute walk distance was 347 m. He underwent 4 weeks of preoperative pulmonary rehabilitation and continued treatment with long-acting bronchodilators. A minimally invasive right upper lobectomy was performed and documented stage 1A non–small cell lung cancer. Two weeks postoperatively, he returned to pulmonary rehabilitation for an additional 8 weeks. Four months postoperatively, his FEV1 had increased to 1.74 L (57% predicted), his FVC was 3.27 (77% predicted), his DlCO was unchanged, and his 6-minute walk distance was 376 m.
[More] [Minimize]Given the hypothesis that lung cancer risk in COPD is related to chronic airway inflammation, inhaled corticosteroids have been considered as possible chemopreventive agents. One multicenter cohort study of patients with COPD conducted in the U.S. Veterans Administration Health System demonstrated a dose-dependent decrease in the risk for lung cancer associated with use of inhaled corticosteroids (20). A meta-analysis of seven randomized trials examining the benefits of inhaled corticosteroids in COPD similarly showed a trend toward decreased lung cancer risk in the inhaled corticosteroid–treated groups (21). However, the analyses were limited by short mean follow-up times, a small number of incident lung cancer cases, and the inclusion of studies not specifically designed to detect differences in incident lung cancer.
A shared genetic susceptibility to development of COPD and lung cancer may be present. Shared genetic loci have been reported on chromosome 6q for both lung cancer risk and reductions in lung function, as well as on chromosome 12 for lung cancer, COPD, and reduced lung function (22). Various studies have implicated numerous genes in the pathogenesis of both COPD and lung cancer, including α1-antitrypsin (23) and microsomal epoxide hydrolase (24, 25), among others. Such possible shared genetic susceptibilities to emphysema and smoking-related DNA damage may additionally contribute to increased aggressiveness of tumor cells in patients with emphysema. For example, tumor progression and metastasis, which require matrix metalloproteinase activity, may be enhanced in emphysematous lungs where an increased abundance of matrix metalloproteinases has been associated with emphysema pathogenesis (26, 27).
Given these strong associations and the unique interplay between lung cancer and COPD, physicians caring for patients with lung cancer occurring in the setting of COPD must account for both diseases when formulating therapeutic plans. This is the focus of the remainder of this review.
A large body of literature supports the use of pulmonary function studies, cardiopulmonary exercise testing, and nuclear perfusion scanning to guide assessment of pulmonary risk and patient selection for lung resection (28, 29). Virtually all patients with COPD fall outside the population of patients who are generally considered safe to undergo lung resection without further investigation (those with both FEV1 and carbon monoxide diffusing capacity [DlCO] greater than or equal to 80% of predicted) (30). For these patients, predicted postoperative FEV1 values (estimated using data from split function lung perfusion scanning and the extent of planned resection) between 700 and 1,000 ml or greater than 30–40% of predicted normal values have been thought to be safe for resection (31). Similarly, a predicted postoperative value for DlCO greater than 40% of predicted normal has been suggested as a safe cutoff (30, 32) (Table 1). Six-minute walk tests and cardiopulmonary exercise testing can further provide information to help physicians estimate the safety and feasibility of resection (30, 32).
|
Criterion |
Value |
|---|---|
| Preoperative FEV1 | >1.5 L or >80% of predicted |
| Preoperative DlCO | >80% of predicted |
| V̇o2 maximum | >15 ml/kg/min |
| Predicted postoperative FEV1 | >40% of predicted |
| Predicted postoperative DlCO
|
>40% of predicted
|
Despite numerous studies suggesting specific numerical cutoff values for safe resection, it is important to consider that progressive developments in anesthetic techniques, minimally invasive surgery, and intensive care unit quality of care all likely contribute to a reduction in postoperative complications and improvement in outcomes. Therefore, surgery may be a viable option for many patients previously considered to be at unacceptably high surgical risk (33).
Sublobar resection for non–small cell lung cancer is an important consideration for patients with COPD, as preservation of lung function in those with extremely low FEV1 might sometimes be better achieved with limited resection. This remains a controversial issue, at least in part due to a lack of randomized clinical trials comparing lobectomy with more modest resections. The only randomized trial to date showed that for T1N0 non–small cell lung cancer (≤3 cm), sublobar resections are associated with higher local recurrence rates, but only trends toward worse overall and cancer-related survival (30% increase, P = 0.08 and 50% increase, P = 0.09, respectively) (10). Complicating the findings, the study contained a mixture of patients undergoing both segmentectomy and wedge resection and also suffered from loss of follow-up of some patients.
Most of the remaining literature comparing segmentectomy and wedge resection with traditional lobectomy involves patients who were poor lobectomy candidates, often because of poor lung function. A meta-analysis concerning survival after lobectomy and limited resection for stage I non–small cell lung cancer (34), as well as a number of prospective nonrandomized studies (some including patients who were deemed fit to tolerate lobectomy), suggest, like the one randomized trial, that 5-year survival rates are not different with limited resection (35–37).
Although a number of retrospective studies also suggest similar survival rates in individuals who have undergone lobectomy versus segmentectomy or wedge resection (9, 38–44), an equally significant body of retrospective evidence demonstrates worse 5-year survival among those who have had sublobar resection (45–49). These disparate findings make clinical interpretation and application difficult and likely result from significant selection bias. Negative studies, with respect to survival, may also be influenced by the size of tumors included for study. Limited resection for tumors less than 2 cm in diameter has, for the most part, been found not to come at the expense of worse survival (37, 47, 49, 50). However, a relatively large study of 100 patients with tumors not more than 1 cm in diameter found that overall 5-year survival was best with lobectomy, intermediate for segmentectomy, and worst for wedge resection, with higher recurrence rates (combined local and distant) seen for wedge resections compared with the larger resections (46).
A study of 1,165 Medicare patients supports the concept that the size of the primary tumor is an important parameter when considering limited resection. Patients who underwent lobectomy or limited resection for stage I lung cancer less than or equal to 2 cm in diameter were evaluated for overall and lung cancer–specific survival, adjusting for patient preoperative characteristics. The adjusted hazard ratios for all cause mortality and lung cancer–specific death for limited resection (performed in 196 patients) were not significantly different from those of lobectomy patients. In the subgroup of individuals with primary tumors between 2 and 3 cm in diameter, limited resection was associated with increased overall and lung cancer–specific mortality.
A total of 2,090 cases of stage I non–small cell lung cancer less than or equal to 1 cm were reviewed through the Surveillance, Epidemiology, and End Results (SEER) registry. There were no significant differences in overall or cancer-specific survival between patients treated by lobectomy and those 688 treated by limited resection (segmentectomy and wedge resection) (51). It is important to note that both segmentectomies and wedge resections were included in the limited resection group in both the Medicare and SEER registries, and retrospective comparisons of wedge resection to segmentectomy have demonstrated worse survival and increased local recurrence with wedge resection (49, 52, 53).
Taken together, available data suggest that limited resections should be avoided in patients who can tolerate lobectomy. Prospective studies that validate the concept that limited resection is equal to lobectomy for patients with tumors less than 2 cm in diameter would be valuable, particularly in the context of patients with COPD with low FEV1. At present, sublobar resection is a reasonable option for a select set of patients who are poor candidates for lobectomy, particularly those for whom low FEV1 presents serious perioperative risks. Even in such patients, segmentectomy should be considered superior to wedge resection.
Since Cooper and colleagues published a favorable report on a series of patients undergoing lung volume reduction surgery for end-stage emphysema (54), clinicians have considered combining lung volume reduction surgery (LVRS) with tumor resection in otherwise traditionally poor surgical candidates. The goal of LVRS is the reduction of lung hyperinflation through resection of poorly functioning, emphysematous portions of lung, allowing for improved exercise tolerance, better bronchial clearance, improved quality of life, and survival (55–57). Numerous case series have suggested that the presence of COPD may significantly affect the relationship between predicted and actual postoperative changes in pulmonary function, even when volume reduction per se is not the primary purpose of the procedure. Table 2 summarizes findings of a number of such studies, particularly as they relate to FEV1.
|
Author, Year (Ref.) |
Number of Patients |
Subjects |
Type of Surgery |
Mean Preoperative FEV1 |
Postoperative FEV1 |
|---|---|---|---|---|---|
| Munoz et al., 1996 (99) | 1 | Left upper lobe malignant nodule | Wedge resection of nodule with resection of separate emphysematous left lower lobe areas | 0.66 L (21% predicted) | 0.70 L |
| Korst et al., 1998 (100) | 32 | 13 with preoperative FEV1 ≤ 60% predicted; 19 with preoperative FEV1 60–80% predicted | Lobectomy | Low FEV1 group: 1.35 L (49% predicted); high FEV1 group: 1.87 L (69% predicted) | Low FEV1 group: 3.7% increase from preoperative value; higher FEV1 group: 15.7% reduction from preoperative value* |
| Sekine et al., 2003 (101) | 521 | 48 patients with COPD, 473 patients without COPD | Lobectomy | COPD group: 1.8 L; non-COPD group: 2.3 L | COPD group: 13.1% reduction from preoperative value*; non-COPD group: change of 29.2% reduction from preoperative value |
| Choong et al., 2004 (60) | 21 | Severe emphysema | Lobectomy or wedge, with or without lung volume reduction in a lobe separate from the tumor | 0.70 L (29% predicted) | 1.0 L (40% predicted) |
| Bobbio et al., 2005 (58) | 11 | Patients with COPD | Lobectomy or bilobectomy | 1.4 L (53% predicted) | 1.4 L (53% predicted) |
| Baldi et al., 2005 (102) | 137 | 88 patients with COPD, 49 patients without COPD | Lobectomy | COPD group: 56% predicted; non-COPD group: 98% predicted | COPD group: 64% predicted†; non-COPD group: 78% predicted† |
| Iwasaki et al., 2005 (103) | 50 | Patients with COPD | Lobectomy (31 patients), segmentectomy (11 patients), bilobectomy (8 patients) | Among subjects with FEV1 ≥ 50 and < 80% predicted:1.53 L; among subjects with FEV1 < 50% predicted: 1.03 L | Decreases in FEV1 were lower than predicted preoperatively |
| Subotic et al., 2007 (104) | 82 | 35 patients with COPD, 47 patients without COPD | Lobectomy and pneumonectomy | COPD group: 1.60 L for lobectomy, 1.91 L for pneumonectomy; non-COPD group: 2.85 L for lobectomy, 2.93 L for pneumonectomy | COPD group: 12% reduction from preoperative value for lobectomy, 18% reduction for pneumonectomy; non-COPD group: 25% reduction from preoperative value for lobectomy,* 43% reduction for pneumonectomy* |
| Schattenberg et al., 2007 (105) | 79 | Patients with COPD | Lobectomy | 1.2 L | 8% reduction from preoperative value immediately after surgery. Values returned to baseline 3 mo postoperatively |
| Kushibe et al., 2008 (106)
|
100
|
30 patients with COPD, 70 patients without COPD
|
Lobectomy
|
COPD with FEV1 ≥ 80%: 2.09 L; COPD with FEV1 < 80%: 1.37 L; non-COPD group: 2.48 L
|
COPD with FEV1 ≥ 80%: 11.6% reduction from preoperative value; COPD with FEV1 < 80%: 4.7% increase from preoperative value‡; non-COPD group: 14.7% reduction from preoperative value
|
This evidence suggests that only minimal decrements (or even improvements) in FEV1 may occur after lung resection in patients with COPD. However, use of spirometry alone may be inadequate as a tool to predict postoperative loss of physical functioning and exercise capacity. One small study of 11 patients with COPD undergoing lobectomy or bilobectomy, mostly for primary lung cancer, demonstrated no significant change in FEV1 or DlCO 3 months postoperatively, but did show a significant decrease in maximal oxygen uptake (V̇o2) from a mean value of 17.8 ml/kg/minute to a mean value of 14.1 ml/kg/minute (58). Similarly, a larger study of 100 patients with COPD and patients without COPD undergoing lobectomy showed that whereas patients with COPD lost less FEV1 than their non-COPD counterparts, the loss of maximal V̇o2 was similar between the patients without COPD and patients with COPD with normal FEV1. However, those with mildly reduced preoperative FEV1 showed smaller relative decreases in maximal V̇o2 postoperatively, and those with the lowest preoperative FEV1 values actually showed an increase in maximal V̇o2 after surgery (59).
Functional improvements after lung resection were also demonstrated in another series in which 21 patients with severe emphysema (mean FEV1 29% predicted and mean DlCO 34% predicted) underwent tumor resection and additional lung volume reduction either via the resection of lung cancer in a severely emphysematous lobe (in 9 patients) or the combination of lobectomy or wedge resection with lung volume reduction surgery (in the other 12 patients) (60). Despite postoperative complications including prolonged air leak in 11 patients and reintubation in 2 patients, these individuals demonstrated an increase in 6-minute walk distances from a mean of 854 ft before surgery to 1,240 ft 6 months postoperatively. This functional improvement was accompanied by significant decreases in the number of patients who required supplemental oxygen after surgery (60).
Unfortunately, radiographic and physiological measurements have not proven to be useful predictors of functional improvement after lung volume reduction surgery. Although the ratio of residual volume to total lung capacity as well as the ratio of upper lobe to lower lobe emphysema were statistically significantly associated with postoperative FEV1 and maximal exercise capacity in the National Emphysema Treatment Trial (NETT), the magnitude of the association was extremely weak, making it difficult to apply to clinical practice (61). Other measures such as inspiratory resistance have shown promise in small series (62) but are not widely clinically available and have not been reproduced in larger studies (61).
Given this uncertainty, determining which patients with COPD should undergo anatomic resection (lobectomy) of lung cancer with our without concurrent lung volume reduction surgery is difficult. Including the radiographic characteristics of the group that benefited most in the NETT (upper lobe–predominant, heterogeneously distributed emphysema) when considering anatomic resection seems the most reasonable approach when evaluating whether patients with COPD and lung cancer are appropriate candidates for lobectomy (57). We recommend that patients with lung cancer and COPD not meeting traditional criteria for safe anatomic resection (i.e., predicted postoperative FEV1 less than 30–40% predicted or predicted postoperative DlCO less than 40%) be considered for lobectomy nonetheless if their tumor is in the upper or middle lobe in an area of significant emphysema, and if the emphysema is upper lobe predominant and heterogeneous in distribution. Such patients can also be considered for concurrent lung volume reduction surgery in the contralateral lung, but it should be emphasized that this approach has not been studied in a systematic manner: True LVRS is a nonanatomically guided surgery that does not observe lobar boundaries whereas combining LVRS with lung cancer resection would involve lobectomy in the lung containing cancer. Because of the lack of data to guide the selection of patients for this approach, we do not advocate that this be performed in current clinical practice. We do suggest that this is an appropriate area for systematic clinical studies to be undertaken, focusing on both intermediate- and long-term outcomes of patients with COPD with lung cancer. In addition, we do not recommend concurrent lung volume reduction surgery at the time of limited resection of lung cancers in nonemphysematous lobes or segments. An illustrative example of lung cancer resection in a patient from our clinical program is presented in Figure 2.
Preoperative functional status may be optimized with appropriate medical therapy, pulmonary rehabilitation, and smoking cessation. Although it seems logical that interventions, such as pulmonary rehabilitation, which improve COPD-specific functional scores (such as the body mass index–obstruction–dyspnea–exercise index [BODE]) (63), might translate into improved perioperative morbidity and mortality, whether this is actually the case has not been tested in clinical studies.
There is a paucity of data to demonstrate that medical optimization improves perioperative outcomes. Medical therapy for COPD can be maximized according to guidelines set by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the American Thoracic Society and the European Respiratory Society guidelines for COPD management (64, 65). Guidelines from these sources include the use of bronchodilators (particularly long-acting), often in combination, as well as inhaled corticosteroids for patients with recurrent COPD exacerbations.
In an analysis of data from the NETT, oral steroid use at the time of surgery was found to be an independent predictor of major cardiac morbidity in a multivariable analysis (66). Although it is possible that use of oral steroid at the time of surgery was a marker for COPD severity or poorly controlled disease (and cardiac disease has been shown to increase with worsening COPD) (67), maximal reduction of systemic corticosteroid to a dose equivalent to 20 mg of prednisone daily is appropriate in preparation for lung volume reduction surgery (68), and was a prerequisite for inclusion in the NETT (69). This likely applies to the patient with COPD undergoing lung resection for lung cancer as well.
A program of rehabilitative exercise has been shown to improve exercise capacity in nonsurgical patients with COPD (70, 71). Such preoperative exercise training may improve V̇o2 sufficiently to move a patient from a physiologically unresectable category (maximal V̇o2 < 10 mg/kg/min) to a potentially resectable one. In the NETT, preoperative rehabilitation was most beneficial in patients who had never participated in a program previously, although changes after rehabilitation were not predictive of differential mortality or improvement in exercise capacity after surgery (72).
No definitive data exist to show that pulmonary rehabilitation alters short- or long-term outcome after lung cancer resection. A study of 22 patients with lung cancer and COPD, and who underwent lobectomy, examined postoperative outcomes after 2 weeks of preoperative aggressive pulmonary exercise and chest physiotherapy (73). These patients had decreased rates of prolonged oxygen supplementation and need for tracheotomy, as well as shorter postoperative hospital stays, compared with 60 historical control subjects who did not undergo rehabilitation. Application of these results is limited by the single-center experience, small sample size, and use of historical control subjects. However, given the safety of pulmonary rehabilitation as well as its documented benefits in nonsurgical patients with COPD, a recommendation of a pulmonary rehabilitation program both before and after lung cancer resection seems appropriate in patients with moderate to severe COPD.
Many patients with COPD are active smokers at the time of cancer diagnosis. Given the relationship between smoking and respiratory complications in the postoperative period (74, 75), smoking cessation has been proposed as a method to reduce perioperative risk. Because a small number of studies have, perhaps paradoxically, suggested an increased risk for postoperative pulmonary complications in patients who quit smoking within 2 months of surgery (74, 76, 77), some physicians have not aggressively advocated smoking cessation in the period immediately before lung cancer resection surgery. Hypotheses proposed to explain the reported increase in risk with smoking reduction or cessation in the immediate preoperative period include nicotine withdrawal and increased volumes of sputum production, which have been observed transiently among recent quitters of cigarette smoking (78). Increased sputum volume may be exacerbated by a concurrent reduction in irritant-induced coughing among those who have recently quit smoking compared with those who continue to smoke (in whom ongoing exposure to irritants in cigarette smoke induces continued coughing and more effective bronchial clearance) (74, 79). Some speculate that this reduction in coughing in recent quitters occurs before recovery of ciliary function and other antimicrobial and antiinflammatory functions of the respiratory epithelium, making recent quitters particularly vulnerable to postoperative pulmonary complications (74). Beyond these possible explanations, it is important to consider the possible effects of selection bias in these observational studies, as sicker subjects at increased risk for postoperative pulmonary complications may have been more likely to reduce cigarette use before surgery (74).
Given the suggested increased risk of pulmonary complications among recent quitters undergoing pulmonary resection in small studies, a prospective study of nonsmokers and smokers undergoing thoracotomy for primary or secondary lung tumors was conducted (80). Three hundred patients were divided into groups of nonsmokers (21%), past quitters of greater than 2 months in duration (62%), recent quitters of less than 2 months in duration (13%), and ongoing smokers (4%). Pulmonary complications occurred in 8, 19, 23, and 23% of these groups, respectively, with no significant difference between the three subgroups of current and former smokers.
Most recently, in-hospital outcomes for 7,990 primary lung cancer resections in the Society of Thoracic Surgeons General Thoracic Surgery Database were evaluated in the context of smoking (81). A multivariable logistic regression model demonstrated an increased risk for in-hospital mortality among both current smokers and recent quitters (those who had quit between 14 d and 1 mo before surgery) compared with nonsmokers (adjusted odds ratios were 3.5 [95% confidence interval, 1.1–11] for current smokers and 4.6 [95% confidence interval, 1.2–18] for those who had quit 14 d to 1 mo before surgery compared with nonsmokers). However, no significant differences in outcomes were reported between recent quitters and current smokers. In addition, those smokers who had quit more than 1 month before surgery did not have statistically significantly increased mortality rates compared with nonsmokers. Pulmonary complication rates, compared with those of nonsmokers, were increased only in those patients who continued to smoke and not in recent quitters (81).
For patients with COPD, the time of lung cancer diagnosis represents a critical window of opportunity for smoking cessation, with studies showing quit rates of 50–60% after diagnosis (82, 83). Compared with patients with lung cancer who continue to smoke, studies have reported improved performance status up to 6 and 12 months after diagnosis among quitters (83), as well as improved overall quality of life, improved appetite, and less fatigue, cough, shortness of breath, lung cancer symptoms, and illness affecting normal activities (82). Smoking cessation has additionally been found to increase both overall and disease-specific survival in lung cancer (84–86).
Because of the opportunity to achieve abstinence from cigarette smoking that is presented by the preoperative period before lung cancer surgery, we strongly recommend that patients quit smoking regardless of timing before surgery, and be provided medical assistance to do so. If possible, delaying surgical resection such that 1 month of smoking abstinence has been achieved may reduce risk of postoperative complications to the level of nonsmokers. However, if it is not feasible to delay surgery, there is no evidence to support the concept that quitting within 1 to 2 months of surgery confers greater risk than continued smoking.
The overall prognosis for patients with COPD and lung cancer is worse than that of patients with lung cancer without COPD (87, 88). Certainly those patients denied surgery, or offered only limited resection because of impaired pulmonary function, may not have the option of surgical cure. In addition, nonsurgical treatment options (limited by scant available supporting data and often reserved for poor surgical candidates) such as radiation therapy (89, 90), radiofrequency ablation (11, 91), stereotactic body radiotherapy (92), and cryotherapy (91) have resulted in poorer survival and increased rates of local recurrence compared with surgical treatment.
The impact of COPD on survival after resection of lung cancer is uncertain. One series demonstrated that for patients with stage I disease and low predicted postoperative FEV1 values (less than 40%), 5-year survival postresection is significantly lower, compared with patients with better lung function (35 vs. 65%) (93). Given that the immediate postoperative mortality and rates of tumor recurrence were similar in the two groups, the increased 5-year mortality in the high-risk group was presumed to be due to nononcological factors. This lower survival rate for patients with severely limited respiratory reserve is consistent with reports by other groups (94, 95).
A retrospective review of patients with pathologic stage IA lung cancer, all treated by complete resection by lobectomy, examined outcomes among patients with and without COPD (96). Frequencies of acute lung injury, bronchial fistula, empyema, and prolonged mechanical ventilation were similar between the 80 patients with COPD and 362 patients without COPD; however, patients with COPD had higher rates of postoperative pneumonia and tracheotomy. Overall survival in the COPD group was significantly worse, with 5-year survivals of 91.6 and 77.0% among patients without COPD and patients with COPD, respectively (P < 0.0001). Of the patients without COPD, 13.5% had recurrence of their lung cancer, whereas 21.3% of patients with COPD had undergone recurrence by 10 years of follow-up. Multivariable analysis of risk factors for disease-free survival documented increased risk related only for tumor size (hazard ratio, 1.775; 95% confidence interval, 1.260–2.501) and the presence of COPD (hazard ratio, 2.079; 95% confidence interval, 1.187–3.641). Results were similar for a multivariable analysis of overall survival. In contrast, a prospective study of 1,370 patients with COPD and 1,558 patients without COPD with surgically treated lung cancer found no difference in overall 5-year survival between patients with COPD and patients without COPD (97). These results are supported by data indicating that smoking status, but not degree of airway obstruction, impacts disease-specific survival in surgically resected stage IA and IB lung cancers (84).
Possibly suggesting an explanation for the seemingly contradictory findings described previously, another report indicates that computed tomography–diagnosed emphysema, but not physiological measurement of airflow obstruction, is associated with decreased overall and disease-specific survival in early-stage lung cancer (98). This study monitored 100 smokers who underwent lobectomy for mostly stage I non–small cell lung cancers. Although there were no differences in pathologic stage or degree of smoking exposure between the patients with and without emphysema, both overall and disease-free survival were better in those with no emphysema (5-yr disease-free survival, 73.6 vs. 44.0%; P = 0.005). In contrast, when patients were stratified by FEV1 (≥70% predicted or <70% predicted), there was no difference in overall or disease-free survival. This finding raises several questions, perhaps most importantly whether emphysema serves as the biological link between COPD and lung cancer more than airway disease.
Given the currently accepted surgical guidelines and often underappreciated limited detriment (and sometimes benefit) of lung resection on lung function in patients with COPD, these patients likely represent a surgically undertreated group. In addition to the standard preoperative evaluation, patients with COPD with potentially resectable lung cancers should be routinely evaluated with anticipation of how such a resection might impact lung function postoperatively specifically in the context of emphysema. Such consideration may serve to widen the pool of surgical candidates and improve prognosis for patients with lung cancer with severe COPD. We suggest that if the primary tumor occurs in the upper or middle lobe in an area of significant emphysema in a patient with heterogeneous distribution of emphysema that is upper lobe predominant, anatomic resection with lobectomy should be strongly considered. If this is not the case, sublobar resection should be considered with segmentectomy preferred over wedge resection.
Until further research offers effective prevention, earlier detection, and/or improved treatment of this devastating disease, physicians must continue to carefully use currently available therapeutic measures. Given that lung cancer, with its relatively poor overall prognosis, is commonly associated with symptomatic and often debilitating COPD, strict attention to quality of life becomes paramount. All patients should receive vigorous counseling regarding smoking cessation—both before and after cancer diagnosis. Medical therapy of COPD should be optimized, with the intention of improving perioperative morbidity and enhancing quality of life. Attention to smoking cessation, pulmonary rehabilitation, and optimal medical therapy can maximize functional status, manage symptoms, and empower patients to take an active role in improving outcomes. Further examination of the biological links between COPD and lung cancer as well as consideration as to whether patients with COPD represent an appropriate group for radiographic lung cancer screening will be critical to reduce the high burden that lung cancer poses on patients living with COPD.
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