Carcinoma of the lung is a fatal disease that, in the

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1 Resection of Lung Cancer Is Justified in High-Risk Patients Selected by Exercise Oxygen Consumption Garrett L. Walsh, MD, Rodolfo C. Morice, MD, Joe B. Putnam, Jr, MD, Jonathan C. Nesbitt, MD, Marion J. McMurtrey, MD, M. Bernadette Ryan, MD, Joseph M. Reising, MD, Kelly M. Willis, MPH, Jeffery D. Morton, MD, and Jack A. Roth, MD Department of Thoracic and Cardiovascular Surgery, Section of Pulmonary and Critical Care Medicine, and Department of Radiotherapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas The medical criteria for inoperability have been difficult to define in patients with lung cancer. Sixty-six patients with non-small cell lung cancer and radiographically resectable lesions were evaluated prospectively in a clinical trial. The patients were considered by cardiac or pulmonary criteria to be high risk for pulmonary resection. If exercise testing revealed a peak oxygen uptake of 5 ml. kg- min-lor greater, the patient was offered surgical treatment. Of the 2 procedures performed, nine were lobectomies, two were bilobectomies, and nine were wedge or segmental resections. All patients were extubated within 24 hours and discharged within 22 days after operation (median time to discharge, 8 days). There were no deaths, and complications occurred in 8 (4%) of the 2 patients. Five patients whose peak oxygen uptake was lower than 5 ml kg- min- also underwent sur- gical intervention; there was one death. Thirty-four patients whose peak oxygen uptake was less than 5 ml. kg- min": and 7 who declined operation underwent radiation therapy alone (35 patients) or radiation therapy and chemotherapy (6 patients). There were no treatment-related deaths, and the morbidity rate was 2% (5/4). The median duration of survival was 48 ± 4.3 months for the patients treated surgically and 7 ± 2.7 months for those treated medically (p =.4). We conclude that a subgroup of patients who would be considered to have inoperable disease by traditional medical criteria can be selected for operation on the basis of oxygen consumption exercise testing. There is a striking survival benefit to an aggressive surgical approach in these patients. (Ann Thorae Surg 994;58:74-) Carcinoma of the lung is a fatal disease that, in the United States, contributes to more than 3% of cancer-related deaths in men and is now the most common cause of cancer-related deaths in women. Of the 7, patients who will be diagnosed with lung cancer this year, more than half will be seen with advanced-stage IIIb or IV disease. Fewer than one third will have resectable tumors confined to the thorax. Surgical resection is the patient's best chance for cure, but many patients are considered inoperable on medical grounds because of inadequate cardiopulmonary functional reserve. The lower limit at which the operative mortality exceeds the benefit of operative intervention has been difficult to define. Although some authors [] have found a 5-year survival rate of up to 35% for patients with stage I disease who are treated with radiation therapy, the overall survival rates in most series of patients who received radiation therapy with or without chemotherapy are low [2, 3]. This study was undertaken to evaluate the effects of surgical and nonsurgical treatments on duration of survival of patients with resectable lung cancer who, because of marginal cardiopulmonary function, would by tradi- Presented at the Thirtieth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 3-Feb 2, 994. Address reprint requests to Dr Walsh, Department of Thoracic and Cardiovascular Surgery, MD Anderson Cancer Center, Box 9, 55 Holcombe Blvd, Houston, TX by The Society of Thoracic Surgeons tionai criteria be considered high risk for lung resection or, by many surgeons, inoperable for medical reasons. Between May 988 and May 993, 66 patients were entered prospectively into this clinical "high-risk" protocol. Material and Methods Eligibility Criteria Patients were eligible for this study if they had histologically proven non-small cell lung cancer, were considered on preoperative clinical and radiologic evaluation to have a resectable tumor, and were deemed to be at high risk for surgical complications because of inadequate preoperative pulmonary or cardiac function or both. "High risk" was defined by conventional pulmonary or cardiac criteria. Pulmonary criteria for entrance in the study included at least one of the following: () forced expiratory volume in second (FEV ) of less than 4% of predicted; (2) predicted postlobectomy FEV of less than 33% of normal predicted value as determined by radioisotopic ventilation/perfusion studies; and (3) resting hypercarbia on arterial blood gas analysis (arterial carbon dioxide tension> 45 mm Hg), Cardiac criteria for entrance in the study included at least two of the following: () myocardial infarction within 3 to 6 months before the evaluation; (2) evidence of class III angina; (3) hemody /94/$7.

2 Ann Thorac Surg 994;58:74- WALSH ET AL 75 namically significant valvular heart disease; (4) atrial fibrillation; (5) age greater than 75 years; (6) history of cerebrovascular accident or transient ischemic attack; and (7) echocardiogram with an ejection fraction of less than.5. The patients were required to give informed written consent to participate in the study. The protocol and consent forms were approved by the University of Texas M.D. Anderson Cancer Center's Office of Protocol Research. Preoperative Evaluation Pulmonary function tests were performed while the patient was at rest in a seated upright position. These tests consisted of spirometry before and after the administration of nebulized bronchodilators, measurement of lung volumes, and carbon monoxide diffusing capacity. The forced vital capacity, FEV, forced expiratory flows at 25% to 75% of forced vital capacity, and maximal voluntary ventilation were determined with a water-sealed spirometer (System 24; SensorMedics, Yorba Linda, CA). Functional residual capacity was determined by body plethysmography. Total lung capacity, residual volume, and residual volume to total lung capacity ratio were calculated. The carbon monoxide diffusing capacity was determined by the singlebreath method. Values were corrected for the hemoglobin level and concomitantly measured alveolar volume. All results were expressed as a percentage of the normal predicted value. The best performance of each patient after bronchodilator administration was used for this analysis. Radionuclide studies of regional pulmonary function were performed while the patient was in a seated upright position and breathing normally at rest. Regional pulmonary blood flow was determined by injection of to 3 mci of radioactive xenon e::xe) dissolved in.9% saline solution. Regional ventilation was determined by inhalation of a tidal volume of a mixture of D3Xe and air. Closed-circuit equilibration with 33Xe determined the relative volume of each lung. The total activity was calculated using data from eight counters, four on each hemithorax. Individual activity from each counter was considered to represent the functional contribution of the corresponding lung zone expressed as a percentage. The calculation of the postlobectomy FEV] (the lobe that contained the tumor) was made using the method described by Ali and co-workers [4]. The arterial blood gas levels, 2-lead electrocardiogram, and M-mode and two-dimensional echocardiograms were obtained while the patient was at rest. The patient's exercise capacity was determined during an incremental exercise test on a cycle ergometer with instantaneous breath-by-breath analysis of gas exchange (CAD/NET System 2; Medical Graphics Corporation, St. Paul, MN). The exercise protocol consisted of a series of -W ramped increases in work every minute until the patient was unable to continue because of severe dyspnea or exhaustion. The patient's heart rate and electrocardiogram were monitored during the exercise study. Infrared digital or earlobe pulse oximetry (Biox 37; Ohmeda Boulder, CO) was used to monitor arterial saturation continuously during exercise and recovery. The peak oxygen uptake (V2peilk) was defined as the highest V 2 achieved during the exercise test. Patients who reached a V 2p m k of 5 ml kg-i. min-- or more during the exercise test were offered surgical treatment. The extent of pulmonary resection (wedge, segment, or lobectomy) was at the discretion of the operating surgeon. Patients whose V2peak was less than 5 ml kg-i. min were considered for radiation therapy with or without chemotherapy as deemed appropriate by radiation therapists and thoracic medical oncologists. Patients received radiation therapy with megavoltage linear accelerators. The planned treatment consisted of 44 Gy applied to the tumor volume with a 2-cm margin. The ipsilateral hilar, mediastinal, and, for upper lobe primary tumors, supraclavicular nodes were included. A boost dose to areas of gross disease consisted of an additional 22 Cy, for a total primary-tumor dose of 66 Gy. Outcome Evaluation All patients enrolled in the protocol were followed prospectively. This included patients whose V2peilk was 5 ml. kg - min-lor higher and who declined operation and patients who, even though their V2peilk was less than 5 ml kg-i. min-i, were still considered by the primary surgeon to be surgical candidates and underwent resection. The date of operation or of the start of medical treatment was considered day. Survival statistics were calculated to May 5, 993. Each patient who underwent surgical intervention was evaluated for nine postoperative complications: () need of postoperative mechanical ventilation for more than 48 hours; (2) myocardial infarction, as evinced by electrocardiogram and elevation in cardiac enzyme levels; (3) cardiac dysrhythmias requiring therapy; (4) roentgenographic evidence of atelectasis or pneumonia; (7) prolonged air leak more than 7 days after operation; (8) angiographically documented pulmonary embolism; and (9) death within 3 days of operation or during hospitalization. Complications related to medical management and radiation therapy were also recorded. Statistical Analysis Differences between the surgical and medical treatment groups were tested for significance by the i' test for categorical variables and the Student t test for continuous variables. Univariate and multivariate analyses of risk factors relating to outcome (survival) were performed using Cox regression. Some of the variables included in the Cox proportional hazards model were believed to have clinical significance even though they may not have represented a significant risk factor in the univariate analysis. Survival differences between the two treatment groups were calculated by the Kaplan-Meier method. A p value of less than.5 was considered significant. Results From May 988 until May 993, 4,798 patients were referred to M.D. Anderson Cancer Center for evaluation and management of newly diagnosed lung cancers. During the

3 76 WALSH ET AL Ann Thorae Surg 994;58:74- Fig 2. Computed tomographic scan. right lower lobe (Figs, 2). The FEV, was 3% of the predicted value, and the estimated postresection FEV I was 2%. Arterial blood gases showed resting hypercarbia (arterial carbon dioxide tension = 47 mm Hg). He was able to exercise to a \'2peak of 2 ml. kg-i. min-. He underwent an uneventful right lower lobe resection with bronchoplasty closure of the bronchus intermedius to retain function of the right middle lobe. The follow-up chest roentgenogram 4 years later demonstrates no evidence of tumor recurrence (Fig 3). Fig. Chest rocntgcnogram showing obstructing squamous cell carcinoma in right lower lobe. Seven patients whose \'2peak exceeded 5 ml. kg" I min -I declined surgical intervention and were treated medically. same period, 976 major thoracic procedures for the resection of bronchogenic carcinomas were performed at the center. Sixty-six patients were evaluated by the high-risk protocol. Two patients, both in the medical group, were enrolled because they satisfied the cardiac criteria and the remaining 64 patients, because they satisfied the pulmonary criteria. Calculations were done with and without the 2 patients enrolled for cardiac factors; because their inclusion did not alter the analysis, they were retained for the overall analysis. Four patients, all in the surgical group, had had previous malignancies but were considered cured and therefore were included in the analysis: patient with Hodgkin's disease 28 years before, with a contralateral Pancoast tumor years before (both were treated with radiation therapy), with a stage I right middle lobe lesion treated by lobectomy 6 years before the development of a second primary in the left upper lobe, and with a head and neck primary tumor resected 5 years before. In another patient in the surgical group, chronic lymphocytic leukemia has developed since resection. Exercise Testing \'2pcak was 5 ml. Twenty-seven kg-i. min I or patients greater during whoseexercise were offered surgical intervention. Twenty accepted and underwent resection. An illustrative case report follows: A 65-year-old man who was seen with hemoptysis had a biopsy-proven squamous cell carcinoma occluding the Fig 3. Chest roentgenogram made 4 years postoperatively showing no evidence of disease.

4 Ann Thorac Surg 994;58:74- WALSH ET AL 77 Table. Clinical Characteristics of Two Patient Groups Surgical Medical Variable (n = 25) (n = 4) P Value Age (y) 66. :': :': Sex (% male) FEV, (%) 4. :': :': 9..9 Xenon 33 (%) 29. :': :': Paco 2 (mrn Hg) 4.4:': :': V2PCilk 5.4:': :': (ml.> kg-i. min- ) FEV = forced expiratory volume in second; Paco, = arterial carbon dioxide tension; VOZp""k = peak oxygen uptake. Thirty-nine patients had a V2peak of less than 5 ml. kg - min-i. Five of them were still considered to be surgical candidates or had no other treatment options because of previous radiation therapy (2 patients already mentioned); they underwent resection. The remaining 34 patients in this group were considered prohibitively high risk by the surgeon and were treated medically. Therefore, the overall surgical group comprised 25 patients, 2 whose V2peak was 5 ml kg-i. min-lor higher, who were offered surgical intervention, and who accepted and 5 whose V2peak was less than 5 ml kg-i. min-i, who were believed on clinical grounds to be surgical candidates or had no other treatment options, and who underwent resection. The overall medical group comprised 4 patients, 34 whose V2pcak was less than 5 ml kg-i. min-i, who were believed by the surgeon to be prohibitively high risk, and who were managed medically and 7 whose V2peak was 5 ml kg-i. min-lor greater but who declined surgical intervention and were managed medically. Demographics Combined demographic and clinical variables for the surgically and medically treated groups are shown in Table. There were no significant differences in age, sex, arterial carbon dioxide tension, FEVI' or predicted postlobectomy FEVI between the two groups. The V2pcak was significantly better in the surgical group (5.4 ::'::: 2.9 ml. kg-i. min-i versus 2.5 :': 2.6 ml kg-i. min-i; p =.2). The two treatment arms were similarly matched in terms of clinical stages, tumor sizes, and histologic types (Table 2). More than 75% of patients in each group had clinical stage I disease. The most common tumor size was T2. Surgical Outcome A total of 25 patients were evaluated. Twenty with a V2pcak of 5 ml kg-i. min-lor higher underwent surgical intervention: 8 had lobectomies, had a lobectomy with bronchoplasty, 2 had bilobectomies (, right lower and right middle lobes, and the other, right upper and right middle lobes with concomitant chest wall resection of ribs 2, 3, and 4), and 9 had segmental or nonanatomic wedge resections. There were no operative deaths. Eight (4%) of the patients experienced complications, including prolonged air leaks (3 patients), atelectasis ( patient), atrial fibrillation (), pneumonia (2), and delirium tremens (). All patients were extubated within 24 hours, often immediately after operation. One patient was initially extubated but required reintubation with the onset of severe delirium tremens and aspiration pneumonia that required prolonged intubation (5 days). The median surgical intensive care unit stay was day (range, to 7 days). The minimum hospital stay was 2 days after operation and the longest, 22 days (median stay, 8 days). One patient underwent a thoracoscopic resection of a T2 lesion in the superior segment of the right lower lobe with complete mediastinal node sampling and was discharged within 2 days. All other patients underwent open procedures. The earliest discharge after a thoracotomy was 6 days (4 patients). The other 5 patients in the surgical group were considered surgical candidates on clinical grounds by the primary surgeon. The average V2peak was only.6 ml. kg-i. min-i (3 patients at ml kg-i. min-i, patient at ml kg-i. min-i, and patient at 2 ml. kg min --I). Four underwent wedge resections and, a trisegmentectomy with chest wall resection. The rates of morbidity and mortality were higher in these 5 patients than in the other 2 in the surgical group. Two patients had an uneventful postoperative course; patient had a prolonged air leak, experienced a neurologic event (aphasia) that resolved in 2 days, and died. The patient who died had had severe pain from a left upper lobe tumor that had invaded the chest wall. The V2peak was only ml kg-l min-- I. Because this patient had been treated with radiation therapy for a contralateral Pancoast tumor years previously and was unable to receive further radiation therapy, he underwent a trisegmentectomy of the left upper lobe with resection of ribs 2, 3, and 4. He was initially extubated, but a pulmonary infiltrate requiring reintubation developed on post- Table 2. Clinical Staging and Histologic Types" Surgical Medical Variable (n = 25) (n = 4) Clinical stage I 2 (8) 3 (75.6) II 2 (8) 2 (4.9) IlIA 3 (2) 89.5) T status T 8 (32) 4(34.) T2 5 (6) 2 (48.8) T3 2 (8) 7 (7.) Histologic type Squamous 6 (64) 2 (5.2) Adenocarcinoma 9 (36) 5 (36.6) Large cell... 5 (2.2) Tumor location LLL 4 (6) 5 (2.2) LUL 9 (36) (24.4) RLL 6 (24) 3 (7.3) RUL 6 (24) 2 (5.2) RML O... 2 (4.9) a Numbers in parentheses are percentages. p Value LLL = left lower lobe; LUL = left upper lobe; RLL = right lower lobe; RML = right middle lobe; RUL = right upper lobe.

5 ' and 78 WALSH ET AL Ann Thorae Surg 994;58:74- Table 3. Summary of Data on Surgical Group Variable Type of procedure Lobectomy (2 LLL, 3 LUL, RLL, 2 RUL) Lobectomy with bronchoplasty (RLL) Bilobectomy (RLL + RML) Bilobectomy with chest wall ribs 2 through 4 (RUL + RML) Anatomic segmentectomy (2 LUL) Segmentectomy with chest wall ribs 2 through 4 (LUL) Nonanatomic wedge resection (2 LLL, 3 LUL, 3 RUL, 3 RLL) Median time to extubation (d) Median SleU stay (d) Median time to discharge (d) Perioperative deaths Value LLL = left lower lobe; LUL = left upper lobe; RLL = right lower lobe; RML = right middle lobe; RUL = right upper lobe; SICU = surgical intensive care unit. operative day 3. Adult respiratory distress syndrome and sepsis subsequently developed, and he died on postoperative day 5. This patient represents the only postoperative death in the surgical group. A list of all surgical procedures performed is given in Table 3. Complete mediastinal lymphadenectomy was done in 22 of the 25 patients, thus permitting accurate postoperative pathologic staging. The pathologic stages were as follows: stage I, 8 patients (6, T NO, and 2, T2 NO); stage II, patient (T2 Nl); and stage IIIA, 3 patients (2, T3 NO, and, T2 N2). The remaining 3 were incompletely staged but comprised 2 T NX and T2 NX. All patients who underwent resection had clear margins except the who died; he had a positive soft-tissue margin where the tumor had invaded the chest wall. Four other patients have died during follow-up. One died at months of unknown causes and, at months of a cerebrovascular accident (the patient with the neurologic event described already) with no evidence of tumor recurrence; died at 3 months with documented tumor recurrence and, at 48 months of respiratory failure after a viral upper respiratory tract infection with no evidence of disease. There are no other known cases of tumor recurrence in this group. Medical Outcome A total of 4 patients were evaluated, 34 with a V2peak lower than 5 ml kg- l. min i 7 with a V2peak higher than 5 ml kg-i. rrdn "! who refused surgical intervention. Treatment in this combined group included radiation therapy alone in 35 and both chemotherapy (cisplatin and etoposide) and radiation therapy in 6. The pretreatment clinical and radiologic staging included 3 in stage I, 2 in stage II, and 8 in stage IIIA. The average age of the group was 67.2 ± 7.5 years, which is not significantly different from that of the surgical group. There were no treatment-related deaths; the morbidity rate was 2% (5/4), and the morbidity included lung abscess ( patient), severe esophagitis (2 patients), esophageal fistula (), and paraplegia () (4%) There have been 24 deaths in this group. Although postmortem examinations were not performed on all patients, at least 2 died with known metastatic disease. Four of the 7 living patients have been documented to have recurrent disease. Survival Curves Kaplan-Meier curves were generated and are shown in Figures 4 through 6. Patients treated surgically had a median survival of 48 ± 4.32 months, whereas those treated medically had a median survival of 7 ± 2.73 months (p =.4). Of the patients whose V2peak was 5 ml kg- l. min-lor higher, those who underwent operation had a median survival of 48 months and those who declined operation had a median survival of 4 months (p =.7). For patients whose V2peak was less than 5 ml kg- l. min-i, operation provided no survival advantage over radiation therapy (p =.79), although the cohort that underwent operation was small (5 patients). A comparison of the median survival for clinical stage I patients treated medically (22 ± 3.3 months) versus surgically shows that surgical intervention yielded a significant survival advantage (p =.64). The median survival for stage I patients treated surgically has yet to be reached over this study period. Univariate and Multivariate Analyses The analysis of survival included the following risk factors: treatment (surgical versus medical), age «7 years versus 2:7 years), sex, FEV I (2:4% versus <4%), l33xe predicted FEVl (2:33% versus <33%), arterial carbon dioxide tension (::;45 mm Hg versus >45 mm Hg), V2peak' clinical stage, T status, and histologic type (Table 4). Both surgical treatment and V2peak of 5 ml kg- l. min-lor higher during exercise performance were significant positive factors for survival (4.74 [p =.4] and 2.5 [p =.4], respectively). In the multivariate analysis, only surgical treatment showed a significant positive relative risk (4.42 [p =.4]) (Table 5). Exercise performance did not further contribute to prediction of survival in this analysis. Comment Surgical intervention remains the best treatment for cure in patients with lung cancer. It has been difficult to assess the lower limit of surgical tolerance of patients with this disease. Several attempts have been made to determine these physiologic limits [5-]. Exercise testing has refined our ability to select patients who will survive even major pulmonary resections, including lobectomies, bilobectomies, and en bloc chest wall resections. Although surgical results may be better because of selection bias, the median survival duration of our patients who underwent operation despite being inoperable by classic medical standards is nearly identical to that of patients with normal pulmonary function who undergo resection. Postoperative pulmonary complications are the leading causes of morbidity and mortality after lung resection [2]. Current preoperative pulmonary function evaluation usually includes spirometry, arterial blood gas levels, and regional pulmonary ventilation/perfusion studies. In some

6 Ann Thorac Surg 994;58:74- WALSH ET AL w >::; «z.6 ;::: :: o, OA :: o..2.8 w ~...J «z.6 ;::: :: Q. OA :: o, MONTHS ~SURGERY 9--B---e XRTTHERAPY Fig 4. Kaplan-Meier curves for patients haoing surgical treatment versus radiation therapy (XRT) MONTHS SURGERY e----b--e XRTTHERAPY FiX 6. Kaplan-Meier curves for patients whose peak oxy:sen uptake was less than 5 ml kg_oj. min ] and who underwent surgical intervention versus radiation treatment (XRT). 5 studies [3, 4], severe impairment of these variables correlates with high rates of postoperative morbidity and mortality. Other studies, however, have not shown ventilation and gas exchange criteria to be predictive of surgical outcome. Cain and co-workers [IS] reported no significant correlation between the degree of preoperative pulmonary function abnormalities and the risk of postoperative complications in patients undergoing thoracotomy. In their study, the mean intensive care unit stay of patients with severe obstructive disease was similar to that of patients with moderate disease. Although some relationship exists between dyspnea and magnitude of impairment of the spirometric variables, a better correlation has been found between dyspnea and exercise studies [6]. This apparent discrepancy between pulmonary function and performance status relates to the fact that exercise capacity is an interactive process that depends on adequate pulmonary function, cardiac status, and peripheral oxygen utilization. The failure of one of these three functions will affect the others, but borderline impairment of one can be compensated by adequate function of the other two. It is possible that patients with marginal pulmonary function can maintain their cardiopulmonary functional status after lung resection because of..8 w >::; «z.6 ;::: :: o, OA :: o, MONTHS ~SURGERY e-e-exrttherapy Fig 5. Kaplan-Meier curves for patients whose peak oxygen uptake was 5 ml kx min-lor higher and who underwent surgical treatment versus radiation treatment (XRT). compensatory cardiac reserves and improved peripheral oxygen utilization. Smith and colleagues [7] evaluated the usefulness of preoperative exercise testing for predicting the incidence of postoperative complications. Exercise capacity measured as the highest oxygen uptake obtained during the study (VOzpcak) strongly correlated with the extent of postoperative complications. The patient's age, history of prior Table 4. Univariate Analysis of Risk Factors for Survival in All Patients Variable Treatment (surgical versus medical) Age «7 y to 2'7 y) Sex (male versus female) FEV, (2'4% to <4%) Xenon 33 (2'33% to <33%) PaC 2 (:545 mm Hg to >45 mm Hg) V2peak (2'5 ml. kg min to < 5 ml. kg'. min- ) Clinical stage Stage I to stage II Stage I to stage III T status T to T2 T to T3 Histologic type (squamous to adenocarcinoma) Relative Confidence Risk Interval p Value FEY = forced expiratory volume in second; PaCOz = arterial carbon dioxide tension; 'VOzpeak = peak oxygen uptake.

7 7 WALSH ET AL Ann Thorac Surg 994;58:74- Table 5. Multivariate Analysis of Risk Factors for Survival in All Patients Relative Confidence Variable Risk Interval p Value Treatment (surgical versus medical) FEV, (2'"4% to <4%) Xenon (2'"33% to <33%) PaC (<;45 mm Hg to > 45 mm Hg) VOzpeilk (2'"5 ml'kg"min-' to < 5 ml. kg r, min- ) Clinical stage Stage I to stage II Stage I to stage III NS T status T to T T to T3.- NS FEV, = forced expiratory volume in second; NS = not significant; PaC 2 = arterial carbon dioxide tension; Y 2 p " a k = peak oxygen uptake. cardiovascular disease, degree of pulmonary impairment, and predicted postoperative FEV were similar in those who experienced pulmonary complications and those who did not. The latter group, however, had a significantly higher V2peak than those who experienced complications. Postoperative complications occurred in all patients with a V2Pcak of less than 5 ml kg-i. min- but in only of the patients whose V2pcak was greater than 2 ml. kg min--. Exercise testing therefore appears to be very useful in the evaluation for the operative risk of thoracotomy [8-2]. Our group of high-risk patients also clearly demonstrates that most patients with marginal pulmonary reserves will tolerate a thoracotomy. All patients in this study who had a V2peak of 5 ml kg-i. min-lor higher survived their operation with acceptable morbidity and no mortality. Patients with a V2pcak less than 5 ml. kg min- had higher rates of morbidity and mortality, but even in this subgroup of high-risk patients, some patients had uneventful postoperative courses. Further refinement of the exercise testing criteria for operability is needed. We have corrected the absolute value of V2pcak for weight (ml.> kg-i. min-). However, additional adjustments to better reflect patient variability (age, height, and sex) can be used in the future to express the V2peak as a percentage of predicted for a given individual. It must also be considered that preoperative evaluation is meant to provide a probability of surgical morbidity and mortality rather than an absolute prediction of outcome. In summary, measurement of V 2 during exercise allowed us to select a subgroup of patients with marginal pulmonary function who tolerated pulmonary resection with acceptable rates of morbidity and mortality. These patients did remarkably well postoperatively and demonstrated a striking long-term survival benefit from this aggressive surgical approach. References. Zhang HX, Yin WB, Zhang LJ, et al. Curative radiotherapy of early operable non-small cell lung cancer. Radiother Oncol 989;4: Dosoretz DE, Katin MJ, Blitzer PH, et al. Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Bioi Phys 992;24: Cooper JD, Pearson FG, Todd TRJ, et al. Radiotherapy alone for patients with operable carcinoma of the lung. Chest 985;87: Ali MK, Mountain CF, Ewer MS, Johnston D, Haynie TP. Predicting loss of pulmonary function after pulmonary resection for bronchogenic carcinoma. Chest 98;77: Markos I. Mullan BP, Hillman DR, et al. Preoperative assessment as a predictor of mortality and morbidity after lung resection. Am Rev Respir Dis 989;39: Olsen GN. The evolving role of exercise testing prior to lung resection. Chest 989;95: Peters RM, Clausen JL, Tisi GM. Extending resectability for carcinoma of the lung in patients with impaired pulmonary function. Ann Thorac Surg 978;26: Wernly JA, DeMeester TR, Kirchner PT, Myerowitz PD, Oxford DE, Golomb HM. Clinical value of quantitative ventilation-perfusion lung scans in the surgical management of bronchogenic carcinoma. J Thorac Cardiovasc Surg 98;8: Ferguson MK, Little L, Rizzo L, et al. Diffusing capacity predicts morbidity and mortality after pulmonary resection. J Thorac Cardiovasc Surg 988;96: Miller JI, Hatcher CR Jr. Limited resection of bronchogenic carcinoma in the patient with marked impairment of pulmonary function. Ann Thorac Surg 987;44: Miyoshi S, Nakahara K, Ohno K, Monden Y, Kawashima Y. Exercise tolerance test in lung cancer patients: the relationship between exercise capacity and postthoracotomy hospital mortality. Ann Thorac Surg 987;44: Schoonover GA, Olsen GN. Pulmonary function testing in the perioperative period: a review of the literature. J Clin Surg 982;: Boysen PG, Block AI. Moulder PV. Relationship between preoperative pulmonary function tests and complications after thoracotomy. Surg Gynecol Obstet 98;52: Ali MK, Ewer MS, Atallah MR, et al. Regional and overall pulmonary function changes in lung cancer. Correlations with tumor stage, extent of pulmonary resection, and patient survival. J Thorac Cardiovasc Surg 983;86: Cain HD, Stevens PM, Adainya R. Preoperative pulmonary function and complications after cardiovascular surgery. Chest 979;76: Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea. Chest 984;85: Smith TP, Kinasewitz GT, Tucker WY, Spillers WP, George RB. Exercise capacity as a predictor of post-thoracotomy morbidity. Am Rev Respir Dis 984;29: Olsen GN, Weinman DS, Boltman JWR, Gass GD, McLain WC, Shoonover GA. Submaximal invasive exercise testing and quantitative lung scanning in the evaluation for tolerance of lung resection. Chest 989;95: Morice RC, Peters EJ, Ryan MB, Putnam JB Jr, Ali MK, Roth JA. Exercise testing in the evaluation of patients at high risk for complications from lung resection. Chest 992;: Bechard D, Wetstein L. Assessment of exercise oxygen consumption as preoperative criterion for lung resection. Ann Thorac Surg 987;44:344-9.

8 Ann Thorae Surg 994;58:74 - WALSH ET AL 7 DISCUSSION DR SHREEKANTH V. KARWANDE (Salt Lake City, trr» I enjoyed your paper. I am interested in whether you looked at more basic exercise tests, such as arterial desaturation. Although your entrance criteria were respiratory variables, for example, forced expiratory volume in second (FEY,), what you actually tested were cardiopulmonary variables. I wonder if you looked at something simpler than maximum oxygen consumption, because I think in this time of cost containment, we might look for a simpler test than the elegant study you did. DR WALSH: The simplest test for patients at high risk for thoracotomy and pulmonary resection is yet to be defined. Simplicity, reproducibility, and cost-effectiveness are laudable goals. Arterial desaturation during exercise is a simple test, but the confidence limits are quite variable. We have examined arterial desaturation in our patients but have not found it to be a reliable predictor of outcome. Substantial desaturation with minimal exertion portends a poor outcome, but minimal change in the oxygen saturation does not guarantee an uneventful surgical course. Stair climbing has commonly been used by thoracic surgeons to select patients for pulmonary resection. Surprisingly, there have been no prospective studies of stair climbing and surgical outcome. These observations are difficult to quantitate (for example, speed and height of stairs) and were not the major focus of this protocol. DR THOMAS R. J. TODD (Toronto, Ont, Canada): I enjoyed that presentation very much. As your criterion of a V 2p ""k of greater than 5 ml kg r, min ',albeit in a small group of patients, led to no deaths, do you think that the Y 2 p e i k measurement cutoff should be adjusted downward? Also, can you share with us any data concerning the exercise tolerance or need of oxygen in the 2 patients who survived operation with an MY 2 greater than 5 ml.v kg "min '? DR WALSH: I briefly mentioned in the manuscript that the absolute number of Y 2p C " k corrected for weight (ml,. kg-'. min- ') may not be the most accurate predictor of postoperative morbidity or mortality. In the future, a percent predicted of Y 2 i ",.' k based on height, age, or sex similar to FEY, reporting may allow us to better characterize this lowest surgical cutoff point. Some of our patients transiently required oxygen in the postoperative period, but no patient required long-term oxygen therapy. DR KENWYN G. NELSON (Tyler, TX): Perhaps this is in the manuscript, but it seems that some of these patients may not have been as high risk as you state. This depends not only on whether bronchodilators were used in the FEV, study (I imagine they were), but also on whether there was a delay in the pulmonary function tests until the patients were either not smoking or without evidence of bronchitis. DR WALSH: Doctor Nelson, your comments allude to our preoperative preparation of patients. All patients who smoke must stop smoking absolutely and completely for a minimum of 2 weeks before operation. If a patient does not comply, the operation is postponed. We record the patient's best FEY, after bronchodilators and repeated testing following the standard guidelines of the American Thoracic Society for reporting pulmonary function results. DR LEWIS WETSTEIN (Freehold, NJ): Doctor Walsh, I congratulate you on a fine presentation. However, my impression is not similar to yours. I disagree with your conclusion because I believe you were not aggressive enough. My colleagues and I reviewed similar data and continue to employ exercise O 2 consumption, but our cutoff is similar to that of Dr Todd, that is, ml kg r, min ] versus your 5 ml kg-' min- l If we evaluate your data, of the 5 patients whose exercise O 2 consumption was less than 5 ml kg'. min-] but whose surgeon thought they would do well regardless, 8% did do well. Moreover, as we all agree that the outcome and the prognosis for these patients are significantly better depending on the method of therapy, that is, operation versus chemotherapy or radiation therapy or both, I would guesstimate that a significant percentage of the other 34 patients would probably have done better if you had been more aggressive. DR WALSH: Doctor Wetstein, our protocol was prospective in nature and approved by our Office of Protocol Research. Patients with a Y 2p C " k of ml kg-']. min ' or less, as you and Dr Bechard have shown, have an operative mortality rate of nearly 3%. Patients with a Y 2p e " k greater than 2 ml kg i min I have been shown to have no mortality. We chose a value OS ml kg t, min ') that is between the two extremes and that has also been used by other surgeons as a basis of exclusion for high-risk resection. We have successfully performed a right upper lobectomy and en bloc chest wall resection of five ribs in a man who had a Y 2p e " k of only 8 ml kg. min I and have also operated on many other patients with a Y 2p ""k of less than 5 ml kg -,. min '; however, we chose our initial value of Y 2 p c " k as 5 ml kg-i. min-i to maximize patient safety in this study. The lowest acceptable Y 2p e " k has yet to be defined and ultimately will rest where the increased risk of surgical intervention outweighs the anticipated survival benefits. The absence of mortality, minimal morbidity, and improved long-term survival after operation in patients with a Y 2p e '" k of 5 ml kg I. min I or greater in this study now justify a further prospective evaluation in patients with even lower exercise test results. Although 8% of our patients undergoing operation with a Y 2 p,," k lower than 5 ml kg. min I survived the operation, they did not demonstrate any long-term survival advantage compared with those treated by radiation therapy. A surgeon's impression and bias that operative survival will directly translate into a long-term survival benefit in this subgroup of high-risk patients to 5 ml kg-i. min ') may not be supported by future careful outcome analysis. DR JEAN DESLAURIERS (Ste-Foy, Que, Canada): I have one comment to add to this well-presented series. Like Walsh and colleagues, my associates and I consider the Y 2m "Xto be of great importance in selecting patients for lung surgery and predicting operative risk. I also think that it is important to measure arterial blood gases (oxygen tension, carbon dioxide tension, and ph) before and during exercise. Desaturation or hypercapnia during exercise is indicative of minimal or no pulmonary reserve and of an increased risk for postoperative morbidity or mortality.