Evaluation of operability before lung resection Chris Thomas Bolliger, MD, PhD

Evaluation of operability before lung resection Chris Thomas Bolliger, MD, PhD Lung resection remains the treatment of choice in the curative approach to nonsmall cell lung cancer. Because most lung cancer patients are current or former smokers, they are at increased risk of chronic obstructive pulmonary disease and coronary artery disease, conditions associated with increased surgical morbidity and mortality. Careful preoperative assessment of the cardiopulmonary reserves is therefore of great importance. Various single and combined parameters for the functional assessment before surgery have been proposed. Currently the emphasis is on the determination of forced expiratory volume in the first second, the diffusing capacity for carbon monoxide, and exercise testing with the measurement of maximal oxygen uptake. Adherence to established algorithms for this preoperative evaluation, advances in operative technique (video-assisted thoracoscopic surgery and combined operations of lung cancer surgery with lung volume reduction surgery), and perioperative care permit resections in patients who until recently would have been considered functionally inoperable. Keywords lung resection, preoperative evaluation, pulmonary function tests, exercise testing Curr Opin Pulm Med 2003, 9:321 326 2003 Lippincott Williams & Wilkins. University of Stellenbosch, Tygerberg, South Africa. Correspondence to C.T. Bolliger, Faculty of Medicine, University of Stellenbosch, 19063 Tygerberg 7505, Republic of South Africa; e-mail: ctb@sun.ac.za Current Opinion in Pulmonary Medicine 2003, 9:321 326 Abbreviations FEV 1 forced expiratory volume in the first second LVRS lung volume reduction surgery ppo predictive postoperative ISSN 1070 5287 2003 Lippincott Williams & Wilkins The ongoing tobacco epidemic has resulted in a dramatic increase in smoking-related disorders, and one of the deadliest diseases in this context is lung cancer, 85 to 90% of which is caused by smoking [1]. It is the most common cancer for both men and women in the United States. Early lung cancer rarely causes symptoms, and when patients start developing them, the disease is usually not curable and treatment is palliative only. At the time of diagnosis, only 15 to 25% of all lung cancers are operable, and despite advances in chemo- and radiotherapy regimens, surgery usually represents the only curative treatment. The workup of patients with suspected or proved bronchogenic carcinoma comprises three entities: tumor type, tumor extent, and cardiopulmonary reserves of the patient (Fig. 1) [2]. The type of the tumor is determined by cytology or histology, which are obtained from sputum cytology, bronchoscopically obtained specimens of cytology or histology, from imageguided transthoracic needle aspirations, or from surgically obtained tissue. The extent of the tumor is assessed by careful staging, which takes radiologic information, mostly by chest CT and more recently combined with positron emission tomography, and clinicopathologic findings into account [3]. The clinical findings of diminished appetite, weight loss, localized pain, or pathologic laboratory results (such as unexplained anemia, elevated erythrocyte sedimentation rate or alkaline phosphatase) can indicate locally advanced or metastatic disease, and may warrant additional imaging studies such as CT of the brain and bone scans. Tumor type and staging determine the carcinologic assessment of the patient. With very few exceptions, small cell lung cancer is treated by chemotherapy and is often supplemented by external beam irradiation. Nonsmall cell lung cancer is staged according to the 1997 TNM classification. Currently, tumors up to stage IIb are considered resectable. Stage IIIa tumors often undergo neoadjuvant chemotherapy and, secondarily, surgery if careful restaging shows response. Stage IIIb and stage IV tumors are unresectable, but ongoing clinical trials may change this approach [4]. When a tumor is considered resectable, curative resection should be attempted, which is rarely less than an entire lobe and often a pneumonectomy. This means resection of a substantial amount of pulmonary parenchyma. Depending on their extent, pulmonary resections lead to permanent loss of pulmonary function [5]. Because most lung cancer patients are smokers, they often present with varying degrees of chronic obstructive pulmonary disease with impaired pulmonary function, and thus increased operative risk. It is therefore important to 321

322 Neoplasms of the lung Figure 1. Algorithm for managing a patient with lung cancer parameters for the functional evaluation, which are discussed in the following paragraphs. Age Increasing age, usually defined as more than 70 years, is associated with complications after pulmonary resections [6 8], but this increased risk is mainly the result of comorbidity in this age group. Patients older than 70 years with a good performance status (Karnofsky score 70 points) and intact cardiopulmonary reserves have a long-term survival comparable with younger surgical patients [9]. Therefore, elderly patients in a good state of health should not be excluded from surgery solely on the basis of their age. The circles represent the three entities that determine the management of a patient with lung cancer. NSCLC, nonsmall cell lung cancer; SCLC, small cell lung cancer; FEV1, forced expiratory volume in the first second; DL CO, diffusing capacity for carbon monoxide; VO 2 max, maximal oxygen consumption. Reprinted with permission [2]. know the functional status of the patient before operating. This functional evaluation or the assessment of operability is the third part of the assessment of a lung cancer patient (Fig. 1), and is the main topic of this review. Parameters of functional operability All functional parameters must be measured when patients are at their best. For pulmonary function tests this often implies an intensive course of antiobstructive therapy, consisting of a systemic steroid trial of approximately 40 mg prednisone daily for 3 to 4 weeks, and inhalational therapy with bronchodilator drugs. Chest physiotherapy and, if possible, a short exercise program should be initiated during the same period. Smoking cessation should be encouraged. The effect of treatment must be analyzed by repeat pulmonary function tests. In lung cancer the natural course of the disease often limits the window for functional improvement to 1or 2 months at the most. Table 1illustrates important currently used Table 1. Parameters for the functional evaluation before lung resection Age Cardiac function Spirometry Diffusing capacity Blood gas measurements Extent of resection Split function studies Exercise testing Cardiac risk Postoperative complications after pulmonary resections are not only the result of pulmonary causes, but are clearly influenced by cardiac comorbidity as well. An abnormal electrocardiogram is associated with an increased risk for sustaining an intraoperative or postoperative cardiac event, defined as heart failure, arrhythmia, or myocardial infarction. A myocardial infarction within the previous 6 months [10], but especially within the previous 3 months [11] is associated with a very high operative risk. If necessary, coronary artery bypass surgery has to be performed before patients with coronary artery disease undergo any other planned surgery. Spirometry Of all the different spirometric parameters and indices recommended in the past, only measurements of the forced expiratory volume in the first second (FEV 1 ) have stood the test of time. Early recommendations of FEV 1 values for safe resections were more than 2 L for pneumonectomy [12] and more than 1.5 L for lobectomy [13]. These values, however, have never been universally accepted, which is easily understandable because they do not take gender, height, weight, and age into consideration, nor do they consider the functional state of the tissue to be removed. Recent interest has therefore shifted to postoperative remaining function. This function, the so-called predicted postoperative (ppo) function, has to be estimated. The techniques used for this estimation are discussed later in the split function section because they are not only used to measure FEV 1 - ppo but also the postoperative diffusing capacity of carbon monoxide (DL CO -ppo) and maximal oxygen consumption on exercise testing (VO 2 max-ppo). Diffusing capacity The DL CO measured with the single-breath technique has gained increasing importance, with values of less than 50% of predicted being regarded as risky [14], and values less than 60% regarded as insufficient for major pulmonary resections [15]. Pulmonary complications are more frequent in patients with a low DL CO [16,17].

Evaluation of operability before lung resection Bolliger 323 In analogy to FEV 1 -ppo, DL CO -ppo has been suggested as a predictor of postoperative complications [18], a concept that is discussed later in the split function section. Blood gas measurements The predictive value of arterial blood gas measurements for functional operability is less than certain. There is no consensus regarding a value of the arterial oxygen tension that would indicate a clearly increased risk for pulmonary resections. For arterial carbon dioxide tension, on the other hand, considerable agreement exists that a raised value of more than 45 mmhg represents an increased risk for pulmonary resections [19,20], but an elevated arterial carbon dioxide tension value alone should not exclude patients from surgery. Extent of resection The estimation of the amount of lung tissue that can be removed safely is very important. There is a clear correlation between the extent of resection, and postoperative morbidity and mortality [21]. Segmental or wedge resections have the lowest risk, and pneumonectomies have the highest risk [22], with the mortality after pneumonectomy usually two times or more than that after lobectomy. By international standards, an overall 30-day mortality rate of ±5% can be considered good and less than 2%, excellent provided that poor-risk patients are not excluded from surgery. Most of these data have been obtained in patient series in which patients have been operated by standard open thoracotomy. Newer techniques such as muscle-sparing thoracotomies or video-assisted thoracoscopy may lower mortality rates further [4]. Split function studies The development of split function studies (or studies of regional lung function) has allowed surgeons to calculate the function of the tissue to be removed relative to the total function of both lungs, and thereby to predict postoperative function. This is important in patients with impaired pulmonary function. The most frequently used postoperative predicted parameter is FEV 1 -ppo, which can be obtained in various ways. The most accurate predictions are obtained with a split perfusion scan using intravenous Tc-99m, or with quantitative CT [23,24 ]. Simple anatomic calculations using the number of segments or subsegments to be removed are less accurate but are often acceptable, provided that a distinction between open and occluded segments is made [24,25]. The formula used for all methods to calculate FEV 1 -ppo is FEV 1 -ppo = preoperative FEV 1 (1 functional contribution of the parenchyma to be resected) For safe resection the FEV 1 -ppo value should be more than 40% of predicted. The use of absolute values should be discouraged because they do not take patient gender, age, and height into consideration. The same formula to predict FEV 1 -ppo has also been used successfully to predict DL CO -ppo [17], as well as VO 2 max-ppo [26]. Interestingly, as for FEV 1 -ppo, a value of less than 40% of predicted normal for both DL CO -ppo [18] and VO 2 max-ppo [26] has been found to indicate increased risk. Exercise testing All parameters discussed so far examine specific aspects of a patient s functional reserves. Exercise testing seems to be an ideal overall parameter for the assessment of cardiopulmonary reserves because it looks at the fitness of a patient, which is an equivalent of cardiopulmonary reserves. During exercise, oxygen consumption, carbon dioxide production, and cardiac output all increase, and the level of work achieved reflects how well the lung, heart, and vasculature interact to deliver oxygen to the tissues. A thoracotomy with pulmonary resection imitates the stress of exercise to a certain extent. Currently, maximal or symptom-limited exercise tests with a cycle or treadmill are recommended. They have the advantage of good reproducibility, assess ischemia with online electrocardiographic monitoring, and are short in duration (usually not longer than 15 20 minutes). The current emphasis is on the measurement of VO 2 max, but in the absence of equipment measuring VO 2 max, Watts can also be used and the VO 2 max values can be calculated. A VO 2 max value of more than 20 ml/kg per minute or more than 75% predicted [27] qualifies for resection up to pneumonectomy, whereas a value less than 10 ml/kg per minute (or less than 40% predicted) is generally prohibitive for any resection. Another frequently used cutoff for safe resection of at least one lobe is a VO 2 max value of 15 ml/kg per minute [17,19,28]. So far, there have been two studies that indicate that VO 2 max-ppo should be more than 10 ml/kg per minute [26,29 ]. In the absence of sophisticated exercise equipment there is considerable evidence that tests of minimal achievements can also be used to estimate the postoperative risk [30]. The most frequently used test by far is stair climbing. The ability to climb three or more flights of stairs [31,32] and five or more flights of stairs [31] has been suggested as a safe indication to undergo resections of a lobectomy and pneumonectomy respectively. Other studies concluded that climbing 4.6 flights (83 steps, 15.35 m) corresponded to a VO 2 max value of 20 ml/kg per minute, which has been shown to qualify for a pneumonectomy [33]. Climbing more than 44 steps was acceptable for high-risk patients [34]. More recently, Brunelli et al. [29 ] suggested that climbing more than

324 Neoplasms of the lung 14 m qualified patients for major resections without any further pulmonary function tests. The current recommendation when using stair climbing is to adhere to a standard protocol during which the patient is encouraged, climbs at a constant speed, does not use railings, and must achieve a predetermined number of flights or height in meters to qualify for a certain extent of resection. Algorithms for the functional evaluation of lung resection candidates Despite increasing enthusiasm for split function studies and exercise testing, one has to remember that many lung resection candidates can undergo resections up to a pneumonectomy without any sophisticated tests, which can be costly and may not be universally available. This stresses the need for an algorithm for preoperative functional evaluation [35]. Figure 2 illustrates such an algorithm: Patients undergo successive steps of functional testing based on the proposed cutoff values until they qualify for varying extents of resection or are deemed inoperable [36]. This algorithm, originally proposed by Bolliger and Perruchoud [37], has been validated [35] and widely accepted. Recently, a simpler algorithm, adapted in part from the one proposed by Bolliger and Perruchoud [37], has been proposed [38] but still needs prospective evaluation. Figure 2. Algorithm for the assessment of the cardiorespiratory reserves of lung resection candidates Patients undergo successive steps from top to bottom until they qualify for varying extents of resection or are deemed inoperable. The safety loop for patients with cardiac problems is indicated in the upper left corner. The dashed line leading from exercise testing back to the cardiac workup is for patients with a negative cardiac history and a normal electrocardiogram (ECG), who show symptoms or signs of ischemia during exercise testing. FEV 1, forced expiratory volume in the first second; DL CO, diffusing capacity of carbon monoxide; VO 2 max, maximal oxygen uptake during exercise; ppo, predicted postoperative. *Consider eligibility for combined tumor resection and lung volume reduction surgery in carefully selected patients. Reprinted with permission [36].

Evaluation of operability before lung resection Bolliger 325 Recent developments The state of the art of lung cancer surgery is still a thoracotomy with careful intraoperative assessment of hilar and mediastinal lymph nodes. There is, however, increasing evidence that video-assisted thoracoscopy is technically feasible [39 ], reduces complications during the postoperative period [4], and that 5-year survival after lobectomy compares favorably with results from open surgery [40 ]. Minimally invasive techniques could therefore become the new gold standard, at least for certain pulmonary resections, which might lead to a further lowering of the cardiopulmonary reserves necessary to qualify for lung resection. The latest development in the field of thoracic surgery is lung volume reduction surgery (LVRS) to improve pulmonary function in patients with severe emphysema [41]. Such patients (deemed inoperable according to the most recent classic pulmonary function tests and exercise parameters, including the algorithm of Figure 2) may become eligible again through a combination of LVRS and simultaneous cancer surgery (see asterisks in Fig. 2). Early reports have shown the feasibility of this approach by removing functionally poor target zones of the lung with LVRS and, concomitantly, pulmonary nodules that were either within or outside these target zones [42,43]. Some of these nodules were stage I lung cancer, and were removed primarily by wedge resection. Recently, Edwards et al. [44] showed that a formal lobectomy could be performed safely in patients with an FEV 1 -ppo value less than 40% but evidence of hyperinflation and emphysema in that lobe. DeMeester et al. [45 ] reported a small series of five high-risk patients who successfully underwent lobectomy of the tumor-bearing lobe in combination with LVRS of one or more additional lobes. Both minimally invasive techniques and LVRS may push the frontiers of functional operability even further than they already are today. In summary, I recommend performing the functional evaluation before lung resection for cancer according to a validated algorithm such as the one depicted in Figure 2. Select patients who are then excluded because of insufficient pulmonary reserves should be evaluated for a combined approach of cancer surgery and LVRS. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: Of special interest Of outstanding interest 1 Wyser C, Bolliger CT: Smoking-related disorders. In The Tobacco Epidemic. Progress in Respiratory Research Edited by Bolliger CT, Fagerström KO. Basel: Karger; 1997, 78 106. 2 Bolliger CT: Pre-operative assessment of the lung caner patient. 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