Effects of presurgical exercise training on cardiorespiratory fitness among patients undergoing thoracic surgery for malignant lung lesions

Authors


  • Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, Georgia, June 2–6, 2006.

Abstract

BACKGROUND.

To determine the effects of preoperative exercise training on cardiorespiratory fitness in patients undergoing thoracic surgery for malignant lung lesions.

METHODS.

Using a single-group design, 25 patients with suspected operable lung cancer were provided with structured exercise training until surgical resection. Exercise training consisted of 5 endurance cycle ergometry sessions per week at intensities varying from 60% to 100% of baseline peak oxygen consumption (VO2peak). Participants underwent cardiopulmonary exercise testing, 6-minute walk (6MW), and pulmonary function testing at baseline, immediately before, and 30 days after surgical resection.

RESULTS.

Five patients were deemed ineligible before surgical resection and were removed from the analysis. Of the remaining 20 patients follow-up assessments were obtained for 18 (90%) before resection and 13 (65%) patients postresection. The overall adherence rate was 72%. Intention-to-treat analysis indicated that mean VO2peak increased by 2.4 mL · kg−1 · min−1(95% confidence interval [CI], 1.0–3.8; P = .002) and 6MW distance increased 40m (95% CI, 16–64; P = .003) baseline to presurgery. Per protocol analyses indicated that patients who attended ≥80% of prescribed sessions increased VO2peak and 6MWD by 3.3 mL·kg−1·min−1 (95% CI, 1.1–5.4; P = .006) and 49 meters (95% CI, 12–85; P = .013), respectively. Exploratory analyses indicated that presurgical exercise capacity decreased postsurgery, but did not decrease beyond baseline values.

CONCLUSIONS.

Preoperative exercise training is a beneficial intervention to improve cardiorespiratory fitness in patients undergoing pulmonary resection. This benefit may have important implications for surgical outcome and postsurgical recovery in this population. Larger randomized controlled trials are warranted. Cancer 2007. © 2007 American Cancer Society.

Pulmonary resection is the treatment of choice for a variety of disorders including nonsmall-cell lung cancer (NSCLC), selected cases of oligometastatic disease (sarcoma, colorectal cancer, melanoma, etc) and some nonmalignant lesions. Despite significant advancements in surgical techniques and postoperative care, complications from pulmonary resection are considerable and largely depend on the extent of resection, the cardiopulmonary reserve of the patient, and the presence of comorbid disease.1, 2 In recent years investigators have demonstrated the role of exercise-based assessments to evaluate medical operability of pulmonary resection patients because this simulates the stresses imposed on the cardiopulmonary system by the operative procedure.1, 3 Among the wide number of exercise-based assessments that are available cardiopulmonary exercise testing (CPET) that includes the measurement of peak oxygen consumption (VO2peak) has been shown to be the strongest independent predictor of surgical complication rate.1, 4–6 Specifically, NSCLC patients with a preoperative VO2peak ≥15 mL · kg−1 · min−1are at comparatively low risk of complications, whereas patients with ≤15 mL · kg−1 · min−1 and ≤10 mL · kg−1 · min−1 are at increased and very high risk of complications, respectively.1, 4–6

Given this evidence, interventions that can improve presurgical VO2peak may have considerable clinical benefit for NSCLC patients undergoing surgical resection. However, to our knowledge to, no reported study has examined the effects of presurgical exercise training in this clinical population. To this end, we conducted a prospective, single-arm feasibility study to examine the effects of presurgical exercise training on preoperative and postoperative markers of exercise capacity including VO2peak relative to body mass (mL · kg−1 · min−1), VO2peak percent predicted, 6-minute walk distance (6MWD), and pulmonary function (PFT) outcomes. We hypothesized that presurgical exercise training would have a beneficial effect on measures of cardiorespiratory fitness before surgical resection.

MATERIALS AND METHODS

Setting and Patients

The study was conducted at the University of Alberta Hospital (UAH), the University of Alberta, and Cross Cancer Institute, Alberta, Canada. Consecutive patients with suspected stage I-IIIA NSCLC, with or without preoperative histologic confirmation who were candidates for primary surgery for curative intent at the UAH were potentially eligible for this study. Patients were deemed not eligible if they had: 1) uncontrolled hypertension, 2) uncontrolled cardiac/pulmonary disease, 3) pulmonary function (forced expired volume [FEV] 1 < 1.1L; diffusion capacity for carbon monoxide [DLCO] adj.) <70% predicted, or 4) contraindications to exercise training based on a cardiopulmonary exercise test. The Alberta Cancer Board and UAH approved the study and written informed consent was obtained from all participants before initiation of any study procedures.

Procedures

Using a prospective, single-group design, potential participants were identified and screened for eligibility via medical record review of surgical candidates at UAH. At the discretion of the thoracic surgeon, eligible patients were provided with a thorough review of the study by the study coordinator and asked if they were willing to participate. Interested participants were then scheduled for a baseline CPET, 6MWD, and a PFT. After the successful completion of the baseline assessments all participants were scheduled for immediate exercise training.

Exercise Training Intervention

The exercise training program was individually tailored to each patient and aimed specifically at increasing VO2peak. All exercise training sessions were supervised by exercise specialists. Exercise training consisted of 5 endurance cycle ergometry (Lifestyle Fitness 9500HR; Life Fitness, Franklin Park, Ill) sessions per week on consecutive days until surgical resection. In Week 1, exercise intensity was initially set at 60% of baseline VO2peak for a duration of 20minutes. Duration and/or intensity were subsequently increased throughout the first week up to 30 minutes at 65% VO2peak. In Weeks 2 and 3, exercise intensity varied between 60% to 65% VO2peak for a duration of 25 to 30 minutes for 4 sessions, in the remaining session patients cycled for 20 to 25 minutes at ventilatory threshold determined by a systematic increase in the VE/VO2 ratio, whereas VE/VCO2 remained constant.7 From the fourth week onwards patients performed 3 sessions at 60% to 65% VO2peak, 1 threshold workout for 20 to 30 minutes, and 1 interval workout. Interval workouts consisted of 30 seconds at peak VO2 followed by 60 seconds of active recovery for 10 to 15 intervals.8–10 All exercise sessions included a 5-minute warm-up and a 5-minute cool-down. Exercise training intensity and safety was monitored continuously via heart rate, blood pressure, and oxyhemoglobin saturation.

Outcomes

The primary outcome was change in VO2peak (mL · kg−1 · min−1) between baseline and immediately before pulmonary resection (presurgery). Secondary exercise capacity outcomes were VO2peak as a percentage of age and gender predicted and 6MWD. Secondary pulmonary function outcomes included FEV in 1 second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), single breath DLCO, and residual volume (RV).

Timing of Assessments

Cardiopulmonary exercise testing, 6MWD, and PFTs were conducted at baseline, immediately presurgery, and postsurgery.

Outcome Assessments

Peak oxygen consumption (VO2peak)

To determine VO2peak, a physician-supervised CPET with 12-lead ECG monitoring (Mac 5000, GE Healthcare) was performed by an exercise physiologist. The specific protocol for this test has previously been reported in detail11 and followed ATS guidelines.12 In brief, tests were performed on an electronically braked cycle ergometer (Ergoline, Ergoselect 100, Bitz, Germany) with breath-by-breath expired gas analysis (Medgraphics, CPX/D system, St. Paul, Minn). Workloads were increased 5–20W/minute until volitional exhaustion or until a symptom limitation was achieved. All participants found the CPET to be feasible, with dry mouth as the only complaint. During exercise oxyhemoglobin saturation was monitored continuously using pulse oximetry (BCI, Hand-Held Pulse Oximeter, Waukesha, Wisc), whereas blood pressure was measured every 2 minutes. Exertional dyspnea and leg discomfort were evaluated at the end of each workload using the modified Borg Scale.

All data were recorded as the highest 30-second value elicited during the CPET. Mean percentage of age- and sex-predicted VO2peak was calculated from the equation provided by Jones et al.13

Six-minute walk test

The 6-minute walk test was conducted according to the guidelines of the ATS.14 Patients were instructed to cover the longest distance possible in 6 minutes under the supervision of an exercise physiologist. The distance walked was determined in a measured corridor, between 2 cones that were placed 30 meters apart. The test was performed twice at each study timepoint with the average recorded. Age- and sex-predicted 6MWD was calculated from the equation of Gibbons et al.15

Pulmonary function test

Spirometry (SensorMedics Vmax22, Yorba Linda, Calif), DLCO, and lung volumes determined by body plethysmograph (6200 Autobox; SensorMedics) were measured in the sitting position according to the ATS guidelines.16

Exercise adherence

Exercise adherence was assessed directly by attendance to the intervention. Exercise performed outside of the program was assessed by self-report using the Godin Leisure Time Exercise Questionnaire (GLTEQ).17 Participants completed the GLTEQ at baseline, presurgery, and postsurgery.

Medical characteristics

Medical data (ie, age, sex, weight, height, smoking history, tumor stage, tumor pathology, and surgery type) was abstracted from medical records. Concurrent comorbid conditions were evaluated using the modified Charlson Index.18 Perioperative and postoperative complications were coded as an adverse event if they occurred within 30 days of pulmonary resection.

Statistical Analysis

Descriptive information was collated on the demographic and medical characteristics of participants and surgical complications. Our primary analysis used a repeated measures analysis of variance (RM-ANOVA) to compare changes in VO2peak from baseline to presurgery. Secondary analyses used RM-ANOVAs to compare changes in secondary outcomes from baseline to presurgery to postsurgery. The principal analysis of primary and secondary study outcomes used the intention-to-treat (ITT) approach. The ITT analysis included all participants recruited to the study (n = 20) regardless of adherence to the intervention. We employed the last-observation-carried-forward procedure for participants who were lost-to-follow-up. In addition, because we also wanted to examine whether change in study outcomes was a function of exercise adherence, we conducted a protocol specified analysis using independent samples Student t tests to examine change in study outcomes based on adherence to the intervention (<80% vs ≥80%). Data were also analyzed with smoking status (ie, current, former, never) entered as a covariate. Data are presented as mean ± standard deviation. All statistical tests were 2-sided and significance was prespecified for P < .05. No adjustment was made for multiple tests.

RESULTS

The study flow is presented in Figure 1. Participant recruitment took place between January 2004 and March 2005. In brief, 43 patients were scheduled for pulmonary resection during the study period. Of these, 35 (81%) met inclusion criteria and 25 (71%) agreed to participate. During the course of the study, 5 (20%) patients were deemed ineligible and were removed from the analysis. Of the remaining 20 patients, 18 (90%) completed the immediate presurgical assessment and 13 (65%) completed the postsurgery assessment.

Figure 1.

Study flow.

Participant Characteristics

The baseline characteristics are shown in Table 1. Mean age was 65 ± 10 years, 70% were women, and mean body mass index was 27 ± 4. Sixty-five percent were diagnosed with NSCLC; 75% underwent a lobectomy, with 15% and 10% undergoing a pneumonectomy and wedge resection, respectively. Patients had a mean VO2peak of 15.7 ± 3.6 mL · kg−1 · min−1 (range: 9.4 to 23.1 mL · kg−1 · min−1) equivalent to 70% of predicted; mean 6MWD was 427 ± 89 (range, 220–606 m) equivalent to 68% predicted. Patients had a mean FEV1, FVC, and DLCO (adj.) of 1.9 ± 0.6, 2.6 ± 0.8, and 18.7 ± 5.9 the equivalent to 73%, 80%, and 81% of predicted, respectively. Mean time from diagnosis to surgical resection was 67 ± 27 days and 51 ± 27 days from surgery to postsurgery follow-up. The average duration of hospital stay was 10 ± 8 days with 8 ± 5 days in general hospital and 2 ± 5 days in the intensive care unit.

Table 1. Characteristics of the Participants (n = 20)
VariableNo. %
  1. SD indicates standard deviation; BMI, body mass index; FEV1, forced expired volume; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume; DLCO, diffusion capacity of the lung for carbon dioxide; DLCO adj., diffusion capacity of the lung for carbon dioxide adjusted for VA; VO2peak, peak oxygen consumption; 6MWD, 6-minute walk distance.

Age, mean ± SD, y 65 ± 10 
Male, %6 30
Weight, mean ± SD, kg 73 ± 12 
BMI, mean ± SD, kg/m2 27 ± 4 
Charlson comorbidity score, mean ± SD 6 ± 2 
Smoking history   
 Current6 30
 Former10 50
 Never4 20
T classification   
 T11 7
 T210 50
 T34 20
 Not applicable5 25
Lymph node classification   
 N0-115 75
 Not applicable5 25
Diagnosis   
 Nonsmall-cell lung cancer13 65
 Small-cell carcinoma2 10
 Other5 25
Extent of resection   
 Wedge2 10
 Lobectomy15 75
 Pneumonectomy3 15
Pulmonary function data   
 FEV1, liters, predicted, (%) 1.9 ± 0.6 (73%) 
 FVC, liters, predicted, (%) 2.6 ± 0.8 (80%) 
 FEV1/FVC, % 71 ± 8 (91%) 
 TLC, liters, predicted, (%) 4.6 ± 1.0 (89%) 
 RV, liters, predicted, (%) 1.9 ± 0.6 (95%) 
 DLCO, L, predicted, (%) 16.9 ± 5.3 (75%) 
 DLCO adj. for VA, L, predicted, (%) 18.7 ± 5.9 (81%) 
Exercise capacity data   
 VO2peak, mL· kg−1.min−1, predicted (%) 15.7 ± 3.6 (70%) 
 6MWD, meters, predicted (%) 427 ± 89 (68%) 
Past exercise behavior   
 Moderate intensity, min 143 ± 273 
 Mild intensity, min 161 ± 242 

Perioperative and Postoperative Complications

Overall, 7 patients experienced complications during the 30-day postoperative follow-up period, an event rate of 35% (7/20). Four patients experienced 1 complication each (ie, thoracic empyema, urinary tract infection, air leak, death), whereas 3 patients experienced 2 complications (ie, respiratory failure and excessive bleeding; thoracic empyema and urinary tract infection; pneumonia and death).

Exercise-Related Adverse Events

Two patients experienced an adverse event during exercise training. Both patients experienced an abnormal decline in systolic blood pressure >20 mm Hg (hypotension) which normalized after exercise discontinuation.

Exercise Adherence

The overall adherence rate was 72% (range, 0%–100%) with patients completing a mean of 30 ± 27 sessions (range, 0–75). There was no significant change in nonprotocol-related exercise over the intervention period.

Intention-to-Treat Analysis

Changes in exercise capacity and pulmonary function outcomes are shown in Table 2. Mean peak oxygen consumption increased 2.4 mL · kg−1 · min−1 (P = .002) from baseline to presurgery. Significant favorable changes were also observed in predicted VO2peak (P <.001), VO2peak (L · min−1) (P < .001), 6MWD (P = .003), and predicted 6MWD (P = .003). No significant change in any pulmonary function outcome was observed from baseline to presurgery (P> .05).

Table 2. Effects on Exercise Capacity and Pulmonary Function (Intention-to-Treat) (n = 20)
VariableBaselinePresurgeryMean difference [95% CI]P
  1. 95% CI indicates 95% confidence interval; VO2peak, peak oxygen consumption; METS, metabolic equivalent; VE, ventilation; RR, respiratory rate; RER, respiratory exchange ratio; SpO2, oxyhemoglobin saturation; 6MWD, 6-minute walk distance; FEV1, forced expired volume in 1 second; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume; DLCO adj., diffusion capacity of the lung for carbon monoxide adjusted for alveolar ventilation.

Exercise capacity    
 VO2peak, mL · kg−1 · min−115.7 ± 3.718.0 ± 3.42.4 [1.0 to 3.8].002
 VO2peak, % pred70 ± 980 ± 1210 [6 to 14]<.001
 VO2peak, L · min−11181 ± 3051314 ± 323133 [71 to 194]<.001
 METS4.6 ± 1.05.2 ± 1.00.5 [0.3 to 0.8]<.001
 Workload, watts82 ± 2491 ± 309 [−0.2 to 18].055
 VE, L · min−145.6 ± 10.950.6 ± 14.45.0 [1.4 to 8.6].009
 RR, breaths · min−131 ± 633 ± 72 [0.3 to 4].029
 Tidal volume, L1514 ± 4181581 ± 47067 [11 to 123].022
 RER1.16 ± 0.101.16 ± 0.080.0 [−0.4 to 0.4].940
 SpO2, %95 ± 295 ± 20 [−2 to 1].266
 Dyspnea3 ± 24 ± 31 [−1 to 2].264
 Leg discomfort5 ± 25 ± 30 [−1 to 2].603
 6MWD, min438 ± 77478 ± 7540 [16 to 64].003
 6MWD, % pred68 ± 1374 ± 146 [2 to 10].003
Pulmonary function    
 FEV1, L1.9 ± 0.61.8 ± 0.6−0.1 [−0.1 to 0.3].470
 FVC, L2.6 ± 0.82.6 ± 0.80.0 [−0.2 to 0.3].770
 TLC, L4.6 ± 1.04.6 ± 1.10.0 [−0.4 to 0.3].850
 RV, L1.9 ± 0.61.9 ± 0.60.0 [−0.3 to 0.4].876
 DLCO (adj.), ml · min−1 · mm Hg18.7 ± 5.918.6 ± 6.1−0.1 [−0.2 to 0.5].431

Per Protocol Analysis

Table 3 displays the changes in primary and secondary outcomes from baseline to presurgery by exercise adherence (<80% vs ≥80%). For patients who achieved ≥80% adherence (n = 12), VO2peak increased 3.3 mL · kg−1 · min−1 (P = .006) and 6MWD increased 49 m (P = .013). Significant beneficial changes were also observed in predicted VO2peak (P <.001), VO2peak (L · min−1) (<.001), peak workload (P = .002), and 6MWD (P = .014). For patients with an adherence rate <80% (n = 8), there were no significant changes in any exercise capacity or pulmonary function outcome except VO2peak predicted (P = .038).

Table 3. Effects on Exercise Capacity and Pulmonary Function (Per Protocol) (n = 20)
 ≥80% adherence<80% Adherence
VariableBaselinePresurgeryMean differencePBaselinePresurgeryMean differenceP
  1. VO2peak indicates peak oxygen consumption; METS, metabolic equivalent; VE, ventilation; RR, respiratory rate; 6MWD, 6-minute walk distance; FEV1, forced expired volume in one second; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume; DLCO adj., diffusion capacity of the lung for carbon monoxide adjusted for alveolar ventilation.

Exercise capacity        
 VO2peak, mL · kg−1 · min−115.3 ± 3.518.6 ± 3.23.3 [1.1 to 5.4].00616.2 ± 4.117.0 ± 4.10.8 [−0.3 to 1.8].129
 VO2peak, L · min−11216 ± 2451412 ± 237196 [115 to 275]<.0011128 ± 3911167 ± 39239 [−23 to 101].177
 VO2peak, % pred70 ± 1181 ± 1411 [6 to 18].00170 ± 677 ± 87 [0.5 to 13].038
 METS4.6 ± 0.95.3 ± 0.80.7 [0.5 to 1.0]<.0014.7 ± 1.24.9 ± 1.20.2 [−0.1 to 0.5].139
 Workload, watts83 ± 1996 ± 2313 [6 to 21].00282 ± 3284 ± 392 [−20 to 23].854
 VE, L · min−147.5 ± 10.054.8 ± 15.37.3 [1.7 to 13.0].01542.8 ± 12.244.3 ± 10.91.5 [−1.6 to 4.5].288
 RR, breaths · min−131 ± 434 ± 83 [0.4 to 5.8].02931 ± 731 ± 40 [−1.6 to 2.3].662
 Tidal volume, L1585 ± 4111659 ± 48374 [−6 to 155].0661409 ± 4361465 ± 45656 [−43 to 155].224
 6MWD, m435 ± 71484 ± 7049 [12 to 85].013442 ± 92467 ± 8725 [−6 to 57].096
 6MWD, % pred69 ± 1077 ± 1314 [2 to 14].01467 ± 1670 ± 163 [1.0 to 8].101
Pulmonary function        
 FEV1, L1.9 ± 0.61.9 ± 0.70.0 [−0.3 to 0.5].4301.7 ± 0.51.7 ± 0.40.0 [−0.3 to 0.3].961
 FVC, L2.7 ± 0.82.6 ± 0.8−0.1 [−0.5 to 0.7].5022.5 ± 0.62.6 ± 0.40.1 [0.3 to −0.1].179
 TLC, L4.7 ± 1.14.6 ± 1.2−0.1 [0.6 to −0.7].6954.4 ± 0.74.4 ± 0.50.0 [−0.1 to 0.1].952
 RV, L1.9 ± 0.71.9 ± 0.80.0 [−0.7 to 0.7].7901.9 ± 0.41.8 ± 0.2−0.1 [−1.0 to 1.2].739
 DLCO (adj.), ml · min−1 · mm Hg20.8 ± 5.220.6 ± 5.3−0.2 [−0.7 to 0.7].66015.0 ± 5.814.8 ± 5.9−0.2 [−1.0 to 1.2].426

Analysis of Covariance

Analyses of covariance indicated that the observed changes in all exercise capacity outcomes across both the ITT and per protocol analyses were independent of smoking status, except ventilation (P = .092, P = .123) and respiratory rate (P = .152, P = .242), respectively.

Exploratory Analysis

Given that patients were lost to follow-up from presurgery to postsurgery, we performed an ancillary analysis of the 13 patients assessed at all 3 timepoints (ie, baseline, presurgery, postsurgery) (Table 4) Among these patients the mean adherence rate was 85%, with patients completing a mean of 33 ± 12 exercise sessions. From baseline to presurgery there were significant beneficial improvements in the majority of exercise capacity outcomes similar to the magnitude observed in the ITT analysis. For the comparison of presurgery to postsurgery, the majority of exercise capacity and pulmonary function outcomes were significantly lower at postsurgery than before surgical resection (P < .05). For the comparison of baseline to postsurgery, no difference in exercise capacity measurements was observed postsurgery compared with baseline but respiratory rate (P = .037) and tidal volume (P = .002) were significantly lower. Regarding pulmonary function, all PFT outcomes, except RV, were significantly lower at postsurgery than at baseline (P's < .05).

Table 4. Effects on Exercise Capacity and Pulmonary Function (Intention-to-Treat) (n = 13)
    Mean difference [95% CI]Mean difference [95% CI]Mean difference [95% CI]
VariableBaselinePresurgeryPostsurgeryBaseline to presurgeryPPresurgery to postsurgeryPBaseline to postsurgeryP
  1. 95% CI indicates 95% confidence interval; VO2peak, peak oxygen consumption; METS, metabolic equivalent; RER, respiratory exchange ratio; SpO2, oxyhemoglobin saturation; VE,BTPS, minute ventilation; RR, respiratory rate; 6MWD, 6-minute walk distance; FEV1, forced expired volume in 1 second; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume; DLCO adj., diffusion capacity of the lung for carbon monoxide adjusted for alveolar ventilation.

Exercise capacity         
 VO2peak, mL · kg−1 · min−116.4 ± 3.819.2 ± 3.016.5 ± 3.92.8 [0.8 to 4.8].010−2.7 [−1.6 to −3.9]<.0010.1 [2.0 to 2.1].950
 VO2peak predicted, %68 ± 979 ± 1367 ± 1410 [4 to 16].002−11 [−6 to −17].001−1 [−8 to 5].702
 VO2peak, L/min1268 ± 2591412 ± 2411175 ± 288144 [80 to 208]<.001−236 [−158 to −314 ]<.001−92 [−190 to 5.3 ].062
 Workload, watts89 ± 21102 ± 2284 ± 2913 [6 to 20].002−17 [−8 to −27].001−5 [−17 to 7].399
 METS4.9 ± 1.05.5 ± 0.84.7 ± 1.10.6 [0.3 to 0.9].001−0.8 [−0.5 to −1.1]<.001−0.2 [−0.5 to 0.1].205
 RER1.20 ± 0.111.22 ± 0.071.18 ± 0.100.01 [0.46 to −0.06].781−0.04 [−0.04 to 0.80].556−0.02 [−0.90 to 0.70].791
 SpO2, %96 ± 295 ± 295 ± 2−1 [−3 to 1].1570 [−1 to 1].956−1 [−3 to 1].245
 VE,BTPS, L/min49 ± 956 ± 1345 ± 126 [12 to 1].031−10 [−15 to −5].001−4 [−10 to 2].173
 RR32 ± 735 ± 834 ± 63 [1 to 5].018−1 [−2 to 3].7032 [−4.9 to −0.1].037
 Tidal volume1609 ± 3761660 ± 4351361 ± 43251 [23 to 124].156−299 [−188 to −409]<.001−247 [−388 to −107].002
 Dyspnea4 ± 34 ± 35 ± 20 [−2 to 1].7061 [−1 to 3].1241 [−1 to 3].173
 Leg discomfort5 ± 25 ± 34 ± 20 [−3 to 1].504−1 [−1 to 3].512−1 [−1 to 3].167
 6MWD, meters461 ± 79505 ± 69461 ± 10143 [9 to 78].017−44 [−6 to 94].0820 [−59 to 60].994
 6MWD, predicted, %72 ± 1180 ± 1272 ± 167 [1 to 13].018−8 [−1 to −16].0780 [−9 to 9].932
Pulmonary function         
 FEV1, liters2.0± 0.51.9 ± 0.51.6 ± 0.5−0.1 [−0.6 to 0.2].247−0.3 [−0.2 to −0.5].001−0.4 [−0.2 to −0.6].002
 FVC, liters2.7 ± 0.62.6 ± 0.62.2 ± 0.7−0.1 [−0.1 to 0.2].507−0.4 [−0.2 to −0.8].003−0.5 [−0.1 to −0.8].010
 TLC, liters4.6 ± 1.04.6 ± 1.14.0 ± 1.10.0 [−0.2 to 0.1].801−0.6 [−0.3 to −1.0].003−0.6 [−0.3 to −1.4].007
 RV, liters1.8 ± 0.71.8 ± 0.71.6 ± 0.50.0 [−0.1 to 0.1].932−0.2 [−0.1 to 0.6].173−0.2 [−0.1 to 0.7].060
 DCLO (adj.)20.7 ± 5.620.4 ± 5.917.6 ± 4.5−0.3 [−0.3 to 1.0].228−2.8 [−1.3 to −5.1].005−3.1 [−1.4 to −5.6].005

DISCUSSION

The principal finding of this study was that presurgical exercise training had a beneficial effect on cardiorespiratory fitness in patients undergoing thoracic surgery for malignant lung lesions. In support of our hypotheses, the ITT analysis indicated that VO2peak increased 2.4 mL · kg−1 · min−1 (14.6%) and 6MWD increased by 40 m (9%), whereas per protocol analyses demonstrated even stronger effects on study outcomes among patients with adherence ≥80% of planned exercise sessions. Among these patients VO2peak increased 3.3 mL · kg−1 · min−1 (21.5%) and 6MWD by 49 m (11%). The magnitude of improvements are higher than those reported in 2 prior studies examining the effects of preoperative home-based exercise training on exercise capacity among patients awaiting surgery for emphysema19 and coronary artery bypass surgery.20 They are, however, consistent with randomized trials of exercise among chronic obstructive pulmonary disease21–24 and chronic heart failure patients,25–28 although this is the first report to demonstrate that a short presurgical exercise training program (4–6 weeks), or ‘prehabilitation’, can lead to similar improvements as longer programs (8–12 weeks) conducted after exacerbation of pulmonary symptoms or surgery.

Our findings may have several implications. First, preoperative exercise could increase the numbers of candidates eligible for curative-intent pulmonary resection. Currently, pulmonary resection is standard care for patients diagnosed with operable NSCLC and other thoracic diseases but is associated with significant complications.1, 2 Given this, CPET to measure VO2peak has become an integral component of risk assessment for pulmonary resection.1, 4, 29 Several prospective investigations and recent systematic reviews have suggested that surgical complications can be stratified by presurgical VO2peak and patients with a VO2peak ≤ 15 mL · kg−1 · min−1 or a 6MWD ≤ 250 m have poor postoperative outcome and are borderline surgical candidates.4, 29 Applying these stratifications to the present study, 9 (45%) would have been considered borderline surgical candidates at baseline. Applying the current findings, assuming a mean improvement of 2.4 mL · kg−1 · min−1 or 40 m in VO2peak or 6MWD (ITT results), only 1 patient would be considered high-risk.

The present study was not powered to determine whether the observed improvements in exercise capacity were associated with lower surgical complications and improved postoperative outcome. The complication rate observed in this study was comparable to numerous prior studies in which mortality and morbidity has been reported to range from 1% to 8% and 20% to 40%, respectively.4 Given that several studies have demonstrated that surgical complications are inversely associated with exercise capacity, interventions that augment VO2peak before surgery may favorably impact clinical management20, 30 and even prognosis. Nonetheless, whether preoperative exercise training reduces perioperative complications remains unknown in this setting. Nevertheless, the present study demonstrates encouraging safety and ‘proof of principle.’ Large prospective randomized controlled trials are required to formally address this question.

Several prospective studies have demonstrated that VO2peak decreases 12% to 20% after pulmonary resection, depending on the type of surgery (ie, lobectomy vs pneumonectomy).31–33 Of significance, our findings indicated that, whereas exercise training resulted in significant improvements in presurgical cardiorespiratory fitness, the majority of outcomes returned to baseline levels approximately 50 days after resection but did not decrease beyond baseline values. Thus, in essence, the intervention completely mitigated the unfavorable functional effects of pulmonary resection on cardiorespiratory fitness. This may have important implications for postsurgical management and patient recovery, particularly those diagnosed with operable NSCLC. Although adjuvant chemotherapy is now standard care after surgical resection, recent trials reported that 5% to 24% of patients received no chemotherapy and only 57% to 69% completed planned therapy.34 Major predictors of therapy initiation and compliance include extent of surgery, age, and performance status. We speculate that a higher exercise capacity after surgical resection might well allow earlier initiation and higher completion rates of adjuvant chemotherapy, and might thereby further improve patient outcome.

As evidenced by the very low training-associated adverse event rate, lack of serious adverse events, and good adherence rate (>70%), a moderate to high-intensity presurgical exercise training appears to be a safe and feasible intervention for patients scheduled for pulmonary resection. Furthermore, our current intervention, which prescribed endurance exercise training 5 days/week, at 60% to 100% VO2peak for 4–6 weeks, produced benefits of similar magnitude to traditional exercise guidelines (3–5 days/week, 30–45 minutes at 50%–75% for 12–15 weeks) in similar clinical populations.25–28 Although 4–6 weeks is a relatively short exercise training period, it is a comparatively long surgical wait time. This extended wait time likely reflects the medical characteristics of the patients enrolled in this study, with many requiring additional presurgical screening and evaluation due to limited cardiopulmonary function and other comorbid conditions (borderline surgical candidates). The long surgical wait time observed in this study may, however, limit the generalizability of our findings. For example, the typical period from diagnosis to resection is 1 to 2 weeks, which is an inadequate period of time to sufficiently impact exercise capacity regardless of the exercise ‘dose.’ Despite this, presurgical exercise interventions may still play an important role in preoperative management of operable candidates. For example, NSCLC patients considered inoperable or borderline at presentation because of poor exercise capacity (≤15 mL · kg−1 · min−1) may be very appropriate for such an approach. Surgery remains the best option for cure for these patients and, thus, surgeons may be willing to delay surgery to improve exercise capacity. Other potential candidates may be operable patients in which surgery is delayed for ≈3 weeks due to active smoking status or other clinical conditions involving major thoracic surgical interventions (eg, esophageal resections, chronic obstructive pulmonary disease, etc). Finally, given that a significant portion of patients with suspected NSCLC will present with impaired exercise tolerance and significant underlying disease, future exercise investigations and/or rehabilitation programs should be conducted in clinic-based, supervised settings (ie, hospital or cancer center). Although this will maximize the safety and efficacy of exercise interventions, such approaches are limited to patients who have transportation and able to attend clinic-based sessions, 3 to 5 days a week for 4 to 6 weeks.

This study does have several limitations. As mentioned previously, the period of time required before pulmonary resection may limit the generalizability of our findings. Other limitations include the nonrandomized design, the relatively small sample size, exclusion of patients with exercise contraindications and significant comorbid disease, and that selection biases are likely to exist because of the transparent purpose of the investigation.

In conclusion, this pilot study demonstrated ‘proof of principle’ that a relatively short, high-intensity, presurgical exercise training program induced significant improvements in exercise capacity among patients undergoing thoracic surgery for malignant lung lesions. Large prospective randomized controlled trials are warranted to definitively address this question.

Acknowledgements

We thank Tyson Kochan, BS, Susan Goruk, BS, and Chris Sellar, MS, for assistance in data collection and analysis.

Ancillary