3430
Safety and Feasibility of Aerobic Training on
Cardiopulmonary Function and Quality of Life in
Postsurgical Nonsmall Cell Lung Cancer Patients
A Pilot Study
Lee W. Jones, PhD1
Neil D. Eves, PhD2
Bercedis L. Peterson, PhD1
Jennifer Garst, MD3
Jeffrey Crawford, MD3
Miranda J. West, BS1
Stephanie Mabe, MS1
David Harpole, MD1
William E. Kraus, MD3
Pamela S. Douglas, MD3
BACKGROUND. A feasibility study examining the effects of supervised aerobic
exercise training on cardiopulmonary and quality of life (QOL) endpoints among
postsurgical nonsmall cell lung cancer (NSCLC) patients was conducted.
METHODS. Using a single-group design, 20 patients with stage I-IIIB NSCLC performed 3 aerobic cycle ergometry sessions per week at 60% to 100% of peak
workload for 14 weeks. Peak oxygen consumption (VO2peak) was assessed using
an incremental exercise test. QOL and fatigue were assessed using the Functional
Assessment of Cancer Therapy–Lung (FACT-L) scale.
RESULTS. Nineteen patients completed the study. Intention-to-treat analysis
indicated that VO2peak increased 1.1 mL/kg21/min21 (95% confidence interval
[CI], 20.3-2.5; P 5 .109) and peak workload increased 9 W (95% CI, 3-14; P 5
Department of Surgery, Duke University Medical
Center, Durham, North Carolina.
.003), whereas FACT-L increased 10 points (95% CI, 21-22; P 5 .071) and fa-
2
intervention. Per protocol analyses indicated greater improvements in
1
Faculty of Kinesiology, University of Calgary,
Calgary, Alberta, Canada.
3
Department of Medicine, Duke University
Medical Center, Durham, North Carolina.
tigue decreased 7 points (95% CI; 21 to 217; P 5 .029) from baseline to postcardiopulmonary and QOL endpoints among patients not receiving adjuvant
chemotherapy.
CONCLUSIONS. This pilot study provided proof of principle that supervised aerobic training is safe and feasible for postsurgical NSCLC patients. Aerobic exercise
training is also associated with significant improvements in QOL and select
cardiopulmonary
endpoints,
particularly
among
patients
not
receiving
chemotherapy. Larger randomized trials are warranted. Cancer 2008;113:3430–9.
2008 American Cancer Society.
KEYWORDS: aerobic exercise, nonsmall cell lung cancer, cardiopulmonary fitness,
quality of life.
This study was supported by funds from the
Lance Armstrong Foundation.
Poster presented at the 44th Annual Meeting of
the American Society of Clinical Oncology,
Chicago, Illinois, May 30, 2008–June 3, 2008.
Address for reprints: Lee W. Jones, PhD, Box
3624, Department of Surgery, Division of NeuroOncology, Duke University Medical Center, Durham, NC 27710; Fax: (919) 684-8203; E-mail:
[email protected]
Received March 20, 2008; revision received May
23, 2008; accepted June 6, 2008.
ª 2008 American Cancer Society
I
mprovements in surgical techniques together with more effective
chemotherapeutic regimens has led to significant survival gains
for individuals diagnosed with localized (operable) nonsmall cell
lung cancer (NSCLC).1 Given improving prognosis, acute and longterm adjuvant treatment sequelae are becoming recognized as important clinical endpoints in the multidisciplinary management of
NSCLC.2
Surgery is the only curative-intent treatment for patients with
localized NSCLC, but postoperative morbidity is considerable.3-5
Resection of the lung parenchyma reduces ventilatory capacity and
reserve. Prospective studies have reported an average reduction in
peak oxygen consumption (VO2peak) of 28% and 13% for pneumo-
DOI 10.1002/cncr.23967
Published online 5 November 2008 in Wiley InterScience (www.interscience.wiley.com).
Aerobic Training in NSCLC/Jones et al
nectomy and lobectomy, respectively, up to 2 years
after resection.3-5 In addition, NSCLC patients are
typically older, are current or former smokers, are
deconditioned, and commonly present with other
concomitant cardiovascular diseases (eg, chronic obstructive pulmonary disease, ischemic heart disease,
etc.). Also, up to 70% of lung cancer patients will
receive either adjuvant locoregional and/or systemic
therapy after resection. The sequential and often
concurrent impact of these factors adversely affects
the integrative ability of the heart, lungs, vasculature,
and circulation to deliver oxygen to the metabolically
active skeletal muscles for adenosine triphosphate
synthesis to drive muscular contraction, which in
turn reduces a patient’s ability to tolerate exercise.
Poor aerobic fitness may lead to increased susceptibility to other common age-related diseases, poor
quality of life (QOL), and likely premature death.6,7
Accordingly, we conducted a feasibility study
examining the effects of supervised aerobic exercise
training on aerobic fitness among NSCLC patients
who had undergone surgical intervention. Secondary
aims were to examine the effects of aerobic training
on QOL and other cardiopulmonary endpoints. We
hypothesized that supervised aerobic exercise training would be a feasible and safe intervention associated with beneficial effects on primary and
secondary study endpoints.
MATERIALS AND METHODS
Setting and Patients
Patients with histologically confirmed stage I-IIIB
NSCLC being treated for curative or palliative intent
at Duke University Medical Center (DUMC) were
potentially eligible for this study. Other major eligibility criteria included 1) Karnofsky performance status 70%, 2) 30 days after surgical intervention, 3)
absence of contraindications to adjuvant chemotherapy, 4) no contraindications to supervised aerobic
exercise training based on cardiopulmonary exercise
testing (CPET),8,9 and 5) primary attending oncologist approval. The DUMC institutional review board
approved the study, and written informed consent
was obtained from all participants before initiation
of any study procedures.
Procedures
By using a prospective, single-group design, potential participants were identified and screened for
eligibility via medical record review of patients
scheduled for their new patient consultation at
DUMC. Immediately after the consultation and
oncologist approval, eligible patients were provided
3431
with a thorough review of the study by the study coordinator and asked if they were willing to participate. Interested participants completed a study
questionnaire, pulmonary function test, and CPET.
After the successful completion of the baseline
assessments, all participants were scheduled for immediate supervised exercise training. After 14 weeks
all baseline assessments were repeated except pulmonary function.
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 American College of Sports Medicine
(ACSM)-certified exercise specialists. Exercise training consisted of 3 aerobic cycle ergometry (Lifestyle
Fitness 9500HR; Life Fitness, Franklin Park, Ill) sessions per week on nonconsecutive days for 14 weeks.
In week 1, exercise intensity was initially set at 60%
of baseline peak workload for a duration of 15 to 20
minutes. Duration and/or intensity were then subsequently increased throughout weeks 2 to 4 up to 30
minutes at 65% peak workload. In weeks 5 and 6,
exercise intensity varied between 60% and 65% of
peak workload for a duration of 30 to 45 minutes for
2 sessions; in the remaining session, patients cycled
for 20 to 25 minutes at ventilatory threshold determined by a systematic increase in the pulmonary
ventilation during exercise (VE)/VO2 ratio, whereas
VE/VCO2 remained constant.10 From the 7th week
onwards, patients performed 2 sessions at 60% to
70% peak workload with 1 threshold workout for 20
to 30 minutes. Finally, in weeks 10 to 14, patients
performed 2 sessions at 60% to 70% peak workload
with 1 interval session. Interval workouts consisted
of 30 seconds at peak workload followed by 60 seconds of active recovery for 10 to 15 intervals.11 All
exercise sessions included a 5-minute warm-up and
5-minute cool down. Exercise training intensity and
safety were monitored continuously via heart rate,
blood pressure, and arterial O2 saturation (SpO2).
Study Endpoints
The primary outcome was change in VO2peak (mL/
kg21/min21) between baseline and postintervention
(14 weeks). Secondary cardiopulmonary fitness endpoints were peak workload, ventilatory threshold,
and O2 pulse. We also examined submaximal
changes in select cardiopulmonary endpoints (ie,
VO2, ventilatory parameters, and heart rate) at an
isotime (ie, 75% of baseline peak workload) during
the incremental exercise test. Secondary QOL endpoints were overall QOL, fatigue, and QOL subscales.
3432
CANCER
December 15, 2008 / Volume 113 / Number 12
Study Endpoint Assessments
Incremental Cardiopulmonary Exercise Testing
To determine VO2peak, an incremental, physiciansupervised CPET with 12-lead electrocardiogram
(ECG) monitoring (Mac 5000, GE Healthcare) was
performed at DUMC by ACSM–certified exercise specialists according to CPET guidelines for clinical8 and
cancer populations.9 All tests were performed on an
electronically braked cycle ergometer (Ergoline, Ergoselect 100, Bitz, Germany) with breath-by-breath
died gas analysis (ParvoMedics TrueOne 2400, Sandy,
Utah). Preceding exercise, 3 minutes of resting metabolic data were collected before participants began
cycling at 20 W. Workloads were then increased 5 to
20 W/min until volitional exhaustion or until a
symptom-limitation was achieved. Workload increments were determined by the medical history of the
participant and metabolic responses to exercise during the first minute. During exercise SpO2 was monitored continuously using pulse oximetry (Hand-Held
Pulse Oximeter, BCI, Waukesha, Wis), and blood
pressure was measured noninvasively by manual
auscultatory sphygmomanometry every 2 minutes.8
At the end of each workload, rating of perceived
exertion was evaluated using the Borg Scale.12 Exercise was terminated if any of the following indications were observed: 1) chest pain, 2) ischemic ECG
changes (S-T segment depression or elevation 0.1
mV), 3) abnormal blood pressure response (>250
mm Hg systolic; >120 mm Hg diastolic; drop in systolic pressure >20 mm Hg), 4) severe arterial oxygen
desaturation (SpO2 85%), and 5) dizziness and/or
nausea. CPET procedures were standardized for all
participants at baseline and postintervention; the
metabolic measurement system was calibrated
before and the calibration was checked after each
test. All data were recorded as the highest 30-second
value elicited during the CPET. Mean percentage of
age- and sex-predicted peak heart rate and VO2peak
was calculated from the equation provided by Jones
et al13 and Fitzgerald et al14 (women) and Wilson
and Tanaka15 (men), respectively.
assesses symptoms commonly reported by lung cancer patients (eg, shortness of breath, weight loss,
tightness in chest). The trial outcome index was
derived from adding scores on the PWB, FWB and
LCS. Fatigue was assessed by the 13-item Fatigue
Scale of the FACT measurement system developed
specifically for the cancer population.17
Exercise Adherence
Exercise adherence was calculated as a percentage
and is equal to the actual number of exercise sessions attended divided by the total number of sessions prescribed (ie, 42). Participants were not
permitted to make-up exercise sessions after 14
weeks. Exercise volume was calculated as intensity
(W) of each exercise session performed multiplied by
the duration (minutes) for the total number of exercise sessions performed during the study.
Medical Characteristics
Medical and demographic data (ie, age, sex, weight,
height, smoking history, tumor stage, tumor pathology, extent of resection, adjuvant therapy) were
abstracted from medical records. Nonprotocol exercise was assessed by self-report.
Statistical Analysis
Under an intention-to-treat principle, analyses
included all enrolled study participants regardless of
adherence to the intervention. The dependent t test
was used to test whether the mean change across
time in the primary and secondary endpoints was
significantly different from zero. The dependent t
test was also used to test whether change in select
primary and secondary endpoints was a function of
adjuvant therapy (received chemotherapy vs no
chemotherapy). A 2-sided alpha of .05 was used for
all tests. Effects are summarized with means and
standard deviations.
RESULTS
Quality of Life
QOL was assessed using the Functional Assessment
of Cancer Therapy–Lung (FACT-L) scale developed
for the assessment of QOL in NSCLC patients.16 The
FACT-L contains 4 general and 1 lung cancer symptom-specific subscales. General subscales include
Physical Well-Being (PWB), Social/Family Well-Being,
Emotional Well-Being, and Functional Well-Being
(FWB). The 7-item Lung Cancer Subscale (LCS)
The study flow is presented in Figure 1. Participant
recruitment took place between January 2006 and
December 2007. In brief, 149 patients attended a
new patient consultation at DUMC during the study
period. Of these, 40 (40 of 149, 27%) met inclusion
criteria and 20 (20 of 40, 50%) agreed to participate.
Of these, 19 (19 of 20, 95%) completed all study procedures. The 1 patient lost-to-follow-up is excluded
from all analyses.
Aerobic Training in NSCLC/Jones et al
3433
FIGURE 1. Study flow is shown.
Participant Characteristics
The baseline characteristics are shown in Table 1.
Mean age was 62 11 years, 53% were male, and
mean body mass index was 26 8 m/kg.2 Seventyone percent underwent a lobectomy, 42% received
adjuvant chemotherapy, and 80% presented with at
least 1 concomitant comorbid disease (47% had
hypertension, whereas 32% had type II diabetes mellitus). Mean forced expiratory volume in 1 second
(FEV1), forced vital capacity, and diffusing capacity of
the lung for carbon monoxide were equal to 71%,
89%, and 83% of predicted, respectively. Mean time
from diagnosis was 30 3 days. No adverse events
were observed during the incremental CPET.
Exercise Adherence
The overall adherence rate was 85% (range, 29%100%), with patients completing a mean of 36 sessions from a total of 42 planned sessions. There was
no change in nonprotocol exercise over the intervention period. No adverse events were observed during
aerobic training sessions.
Intention-to-Treat Analyses
Changes in cardiopulmonary fitness endpoints are
shown in Table 2. No significant changes in any cardiopulmonary endpoints at rest were observed from
baseline to postintervention. Mean VO2peak increased
1.1 mL/kg21/min21 (95% confidence interval [CI],
20.3-2.5; P 5 .11), and peak workload increased 9 W
(95% CI, 3-14; P 5 .003). For submaximal exercise
isotime responses, VO2, ventilation, or heart rate
were generally lower at the same relative workload
(75% of baseline peak workload) in the postintervention incremental CPET; however, none of these
changes reached statistical significance (P > .05).
Table 3 displays the changes in QOL endpoints.
Mean FACT-L, FACT-General (FACT-G), and trial outcome index increased 10 points (95% CI, 21-22; P 5
.07), 8 points (95% CI, 22-19; P 5 .09), and 9 points
(95% CI, 1-17; P 5 .03), respectively. Significant favorable changes were also observed for functional wellbeing (P 5 .007) and fatigue (P 5 .03), and the lung
cancer subscale (P 5 .10) approached significance.
Per Protocol Analysis
Changes in select primary and secondary study endpoints by chemotherapy (received chemotherapy vs
no chemotherapy) are presented in Table 4. Exercise
adherence was 93% and 72% for patients receiving
and not receiving chemotherapy, respectively. For
patients not receiving adjuvant chemotherapy (n 5
11), VO2peak increased 1.7 mL/kg21/min21 (P 5 .008).
Significant increases were also observed for peak
heart rate (P 5 .05), peak workload (P < .001), and
workload at ventilatory threshold (P 5 .05). Changes
in submaximal exercise isotime responses were not
statistically significant (P < .05). Concerning select
QOL endpoints, for patients not receiving adjuvant
chemotherapy, significant increases were observed
for all QOL outcomes except the lung cancer subscale (P 5 .22). For patients receiving adjuvant chemotherapy (n 5 8), there were no significant changes
in any cardiopulmonary or QOL outcome (P > 0.05),
except VO2peak at ventilatory threshold, which significantly decreased over the study period.
3434
CANCER
December 15, 2008 / Volume 113 / Number 12
TABLE 1
Characteristics of the Participants (n519)
Variable
Age, y
Men, %
Weight, kg
BMI, kg/m2
Smoking history
Current
Former
Histologic features
Adenocarcinoma
Squamous
Undifferentiated
Stage
IA
IB
IIA
IIB
IIIA
IIIB
Extent of Resection*
Lobectomy
Pneumonectomy
Bilobectomy
Wedge
VATS
Bronchoscopy
Adjuvant therapy
Received Chemotherapy
Received Radiotherapy
Concomitant comorbidities*
Coronary artery disease
Type II diabetes mellitus
Hypertension
Hyperlipidemia
Asthma
Atrial fibrillation
Osteoarthritis
Pulmonary function data
Predicted FEV1, L (%)
Predicted FVC, L (%)
FEV1/FVC, %
Predicted TLC, L (%)
Predicted RV, L (%)
Predicted DLCO, L (%)
No. (%)
Mean6SD
6211
10 (53)
7616
268
2 (11)
17 (89)
12 (63)
5 (26)
2 (11)
8 (42)
3 (16)
2 (11)
2 (11)
—
4 (21)
12 (71)
1 (6)
1 (6)
1 (6)
1 (6)
3 (18)
8 (42)
1 (5)
3 (16)
6 (32)
9 (47)
5 (26)
1 (5)
2 (10)
2 (10)
2.20.5 (71)
3.70.9 (89)
6211
6.31.6 (98)
2.61.6 (115)
19.25.8 (83)
*Numbers do not equal 100% because of overlap between categories.
BMI indicates body mass index; VATS, video-assisted thoracoscopic surgery; FEV1, forced expired
volume; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume; DLCO, diffusion
capacity of the lung for carbon dioxide.
DISCUSSION
The principal finding of this pilot study was that a
short-term, moderate to high-intensity supervised
aerobic exercise training program was feasible, safe,
and well tolerated among newly diagnosed NSCLC
patients who had recently undergone surgical intervention. Moreover, analyses indicated significant
improvements in QOL and select cardiopulmonary
endpoints, particularly among patients not receiving
chemotherapy. To our knowledge, this is the first
study to examine the independent effects of aerobic
training among this patient population in this
setting.
Several recent randomized trials have examined
the effects of exercise training as an adjunct supportive therapy in a broad range of cancer patients differing in terms of cancer diagnosis, disease stage, and
treatment.18-21 Overall, the extant literature indicates
that exercise training is safe and well tolerated
among oncology patients. It is not clear, however,
whether the low incidence of events reflects the true
safety or less than optimal exercise test methodology
and/or data reporting in clinical oncology research.9
Consistent with these findings, we observed no
adverse events during the incremental CPET or
supervised exercise training sessions. Moreover, adherence to exercise training was excellent (85% of
planned sessions) and above conventionally accepted
levels for exercise intervention trials in clinical populations.22 Patients in this study were older, had poor
exercise tolerance, presented with a diverse range of
concomitant comorbidities, had recently undergone
surgical excision of lung tissue, and almost 1-third
were receiving platinum-based chemotherapy. Thus,
demonstration of the feasibility and safety of moderate- to high-intensity aerobic training in the present
context is novel and important.
A second important finding of this study was the
significant improvements in patient-reported outcomes (PROs). Results indicated that global QOL
scores increased 8 to 10 points over the course of the
intervention, with even stronger changes among
patients not receiving chemotherapy. These findings
may have important clinical significance. In a recent
systematic review of 39 studies (12 were among lung
cancer patients) involving 13,874 cancer patients,
Gotay et al reported that PROs, especially QOL, provided prognostic information beyond conventional
clinical assessments (eg, performance status, stage,
etc.).23 Furthermore, a change of 4 points or more in
the FACT-G is considered the minimal clinically important difference (CID).24 The CID for fatigue (ie, a
10-point change) was also achieved in the per-protocol analysis.24 The majority of, but not all, studies
have also reported significant improvements in
PROs, particularly global QOL and fatigue, after exercise training in the oncology setting.18-21 The
mechanisms underlying the improvements in PROs
with aerobic training are not known. Courneya et al
reported that change in VO2peak was strongly correlated with change in QOL after aerobic training
among breast cancer patients.25 In this study,
Aerobic Training in NSCLC/Jones et al
3435
TABLE 2
Mean Changes in Cardiopulmonary Endpoints (n519)
Variable
Primary
VO2peak, mL/kg21/min21
Secondary
VO2peak, L/min21
Predicted VO2peak, mL/kg21/min21, %
Workload, W
Heart rate, beats/min21
Predicted heart rate, beats/min21, %
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
O2 pulse, mLO2/beat
METS
RER
VE, L/min
RR
Tidal volume, L
SpO2, %
RPE
VO2, at VT, mL/kg21/min21, %
Workload at VT, W
Reason for test termination, n (%)
Leg fatigue
Dyspnea
Both
Baseline, Mean6SD
Postintervention, Mean6SD
Mean Difference [95% CI]
P
15.73.3
16.83.9
1.1 [20.3 to 2.5]
.11
1.160.3
62
749
1243.7
76
16420
817
132
4.50.9
1.060.04
4510
338
1.40.4
954
162
719
6125
1.260.3
66
8322
13019
80
16220
807
132
4.91.1
1.080.09
4912
325
1.60.4
953
172
7010
6418
0.10 [20.01 to 0.19]
4 [20.9 to 10]
9 [3 to 14]
6 [20.4 to 13]
4 [20.2 to 8]
22 [214 to 10]
21 [23 to 1]
0 [20.6 to 1.2]
0.4 [20.02 to 0.81]
0.02 [20.02 to 0.06]
4 [20.1 to 7]
21 [24 to 2]
0.2 [0.02 to 0.19]
0 [21.4 to 1.1]
1 [20.5 to 2]
21 [26 to 3]
3 [26 to 12]
.10
.10
.003
.06
.06
.74
.40
.52
.06
.28
.06
.69
.01
.80
.23
.58
.52
8 (42)
7 (37)
4 (21)
9 (47)
6 (32)
4 (21)
—
—
—
—
—
—
Data are presented as mean standard deviation (SD).
CI, confidence interval; VO2peak, peak oxygen consumption; METS, metabolic equivalent unit; RER, respiratory exchange ratio; VE, ventilation; RR, respiratory rate; SpO2, arterial oxygen saturation; RPE, regular
pulse excitation; VT, ventilatory threshold.
TABLE 3
Mean Changes in Quality of Life Endpoints (n519)
Variable
Global scores
FACT–Lung (0-136)
FACT–General (0-108)
FACT trial outcome index (0-84)
Subscales
Physical well-being (0-28)
Functional well-being (0-28)
Social well-being (0-24)
Emotional well-being (0-28)
Fatigue (0-52)
Lung cancer subscale (0-28)
Baseline, Mean6SD
Postintervention, Mean6SD
Mean Difference [95% CI]
P
9818
8016
5612
10814
8813
6410
10 [21-22]
8 [22-19]
9 [1-17]
.07
.09
.03
206
175
253
185
198
194
235
205
245
203
128
212
3 [21-8]
4 [1-6]
21 [22-3]
2 [21-5]
27 [21 to 217]
2 [21-5]
.15
.007
.85
.27
.03
.11
Data are presented as means standard deviation (SD).
CI, confidence interval; FACT, Functional Assessment of Cancer Therapy.
changes in cardiopulmonary endpoints were not
associated with changes in any PRO. Thus, other factors, including social interaction (between participants and study personnel), improvements in
physical competence and self-confidence, positive
feedback, coping with their cancer diagnosis and
treatment, and distraction, may explain our results.
An intriguing finding of this study was that
although intention-to-treat analyses indicated a nonsignificant improvement in VO2peak per-protocol
analyses indicated that this improvement was largely
restricted to those patients not undergoing chemotherapy. Improvements in VO2peak were 0.3 mL/kg21/
min21 or 2% in patients receiving chemotherapy.
3436
CANCER
December 15, 2008 / Volume 113 / Number 12
TABLE 4
Mean Changes in Cardiopulmonary and Quality of Life Endpoints by Adjuvant Therapy (Chemotherapy vs No Chemotherapy) (n519)
Variable
Cardiopulmonary endpoints
Primary
VO2peak, mL.kg21.min21
Chemotherapy
No chemotherapy
Secondary
Heart rate, beats/min21
Chemotherapy (n58)
No chemotherapy (n511)
VO2peak, mL/min21
Chemotherapy
No chemotherapy
Workload, W
Chemotherapy
No chemotherapy
VO2 at VT, mL/kg21/min21, %
Chemotherapy
No chemotherapy
Workload at VT, W
Chemotherapy
No chemotherapy
Quality of life endpoints
FACT–Lung (0-136)
Chemotherapy (n58)
No chemotherapy (n511)
FACT–General (0-108)
Chemotherapy
No chemotherapy
FACT trial outcome index (0-84)
Chemotherapy
No chemotherapy
Fatigue (0-52)
Chemotherapy
No chemotherapy
Lung cancer subscale (0-28)
Chemotherapy
No chemotherapy
Baseline, Mean6SD
Postintervention, Mean6SD
Mean Difference [95% CI]
P
16.72.9
15.03.5
17.03.7
16.74.1
0.3 [23 to 3]
1.7 [0.6 to 3.0]
.84
.008
13520
11618
13814
12520
3 [210 to 15]
11 [21 to 19]
.63
.05
1.260.3
1.100.2
1.270.4
1.250.3
0.01 [20.23 to 0.26]
0.15 [0.05 to 0.24]
.94
.007
8327
6923
8527
8220
2 [27 to 12]
13 [8 to 19]
.55
<.001
698
729
637
7411
26 [211 to 21]
2 [20.7 to 4.5]
.03
.48
6816
5519
5820
6719
210 [221 to 3]
12 [1 to 24]
.12
.05
997
9723
9911
11412
0 [215 to 14]
17 [22 to 1]
.97
.05
805
7820
7910
9310
21 [214 to 11]
15 [1 to 29]
.82
.05
565
5516
5910
688
3 [29 to 15]
13 [1 to 25]
.52
.04
184
2010
167
107
22 [210 to 7]
210 [218 to 22]
.62
.03
193
195
201
223
1 [21 to 4]
3 [22 to 7]
.23
.22
Data are presented as mean standard deviation (SD).
CI indicates confidence interval; VO2peak, peak oxygen consumption; VT, ventilatory threshold; FACT, Functional Assessment of Cancer Therapy.
Clearly, without a nonintervention control group, it is
not known whether maintenance of VO2peak during
chemotherapy is important. The direct effects of
NSCLC chemotherapeutics on cardiopulmonary
function are not fully known, although platinumbased regimens cause reductions in FEV1 and anemia,26,27 which are expected to attenuate normal
physiologic adaptations to aerobic exercise training.
Accordingly, based on the current evidence, further
study of aerobic training among patients undergoing
adjuvant chemotherapy does not appear warranted
at this time.
In contrast, the improvement in VO2peak was 1.7
mL/kg21/min21 or 11.3% among those not receiving
chemotherapy. Following traditional aerobic exercise
training guidelines (3-5 days/week at 50% to 75% of
baseline VO2peak for 12-15 weeks), an 15% improvement is the generally accepted ‘‘clinically important’’
change in VO2peak in noncancer populations.28,29 In
noncancer populations, cardiopulmonary fitness has
become established as a strong, independent predictor of mortality across a broad range of adult
patients with chronic disease.6,7,30 No study to date
has examined the prognostic value of cardiopulmonary fitness on survival in patients with lung cancer.
Nevertheless, subjective measures of functional capacity (a surrogate of cardiopulmonary fitness) used in
lung cancer management (ie, performance status
scoring systems) are consistent predictors of mortality.31-34 Although the magnitude of VO2peak improve-
Aerobic Training in NSCLC/Jones et al
ment was below the accepted ‘‘clinically important’’
change, given the well-established clinical value of
VO2peak and Karnofsky performance status, we
believe that these results warrant further investigation. Moreover, given that the prognostic value of
VO2peak in lung cancer is not known, an improvement of 11% may in fact be meaningful, especially
in the context of severe deconditioning and high
postsurgical morbidity. Prospective, observational
studies are required to fully address this question.
Of importance, although per-protocol analyses
indicated significant improvements in VO2peak among
patients not undergoing chemotherapy, the magnitude of benefit was modest (11%). Our group
recently reported that presurgical aerobic exercise
training (cycle ergometry, 5 days/week at 60%-100%
VO2peak) was associated with a 15% to 22% improvement in VO2peak among 20 patients with suspected
NSCLC.11 The contrasting findings may be explained
by differences in exercise prescription and/or limitations to exercise between the 2 studies. In our presurgical study, aerobic training consisted of 5 cycle
ergometry sessions/week over 4 to 6 weeks (30
exercise sessions) compared with 3 cycle ergometry
sessions/week over 14 weeks (42 sessions) in this
study. Although the total exercise volume was higher,
the relative exercise ‘‘dose’’ was higher in the presurgical study, given the greater frequency of sessions/
week over a shorter period. These results suggest
that a high-exercise ‘‘dose’’ may be required to
induce favorable adaptations in NSCLC patients who
are severely deconditioned after surgical resection
and related disease pathophysiology. The significant
correlation between exercise volume and change in
VO2peak (r 5 0.54, P 5 .02) observed in this study
support this notion (data not presented).
The contrasting findings may also be associated
with greater exercise limitations among patients after
extensive pulmonary resection. An obvious potential
explanation is a ventilatory limitation or inadequate
gas exchange after removal of a substantial portion
of lung parenchyma. However, several elegant studies
have demonstrated that VO2peak is not limited by
ventilation or diffusion capacity.35-38 Indeed, our
results corroborate these findings, as only 4 individuals demonstrated any evidence of ventilatory limitation,8 and only 1 had an oxyhemoglobin saturation
at peak exercise <90%. Thus, improvements in other
components involved in O2 transport39 must contribute to the modest improvements in VO2peak after
aerobic training observed here.
Other potential limiting mechanisms include
decreased cardiac output and/or peripheral muscle
limitation.39 In this study, 65% of patients subjec-
3437
tively reported leg fatigue or a combination of leg fatigue and dyspnea as the major symptom(s)
responsible for exercise termination. These findings
indicate that O2 delivery and/or skeletal muscle limitation may contribute to the reduced VO2peak. Skeletal muscle limitation is well documented in chronic
obstructive pulmonary disease (COPD) patients who
exhibit similar disease etiology and symptoms as
patients with NSCLC.40 However, it is currently not
known whether skeletal muscle limitation is because
of muscle dysfunction per se or muscle weakness
because of deconditioning (disuse).41 Major contributors to skeletal muscle dysfunction in COPD include
direct skeletal myopathy (from the use of oral corticosteroids), and high levels of systemic inflammation
and oxidative stress (from underlying disease and
therapy).41 Importantly, NSCLC patients are also
deconditioned, receive corticosteroids, and have high
levels of systemic inflammation.42 The contribution
of these factors to exercise intolerance in NSCLC
requires investigation.
Given all the above, exercise training programs
that target both central and peripheral factors limiting exercise tolerance in NSCLC will be required to
ensure optimal improvements in VO2peak. The combination of resistance and aerobic training may provide
the optimal solution. In COPD, standard resistance
training guidelines (ie, 3-5 times/week, 50%-75% of 1
repetition maximum for 12-24 weeks) have been
demonstrated to improve skeletal muscle oxidative
capacity, muscle endurance, and strength, as well as
whole body exercise tolerance (VO2peak and 6-minute
walk distance).40 It is postulated that the improvements in skeletal muscle function and strength from
resistance training will not only have independent
effects on aerobic fitness, but will allow patients to
perform aerobic exercise training at higher intensities
to elicit greater improvements in exercise tolerance
and health-related QOL than either alone.
This study does have limitations, including the
relatively small sample size, the nonrandomized
design, and the exclusion of patients with contraindications to aerobic training and significant comorbid
disease. Thus, significant patient selection bias likely
exists because of the transparent nature of the study,
with patients highly motivated to exercise and having
better prognosis being more likely to participate.
Indeed, only 13% of screened patients were actually
recruited. However, although we likely recruited a
highly motivated cohort of patients, only 10% of
patients met national exercise guidelines (data not
presented) and VO2peak was, on average, 38% below
that for age- and sex-matched sedentary individuals14,15 and comparable to that reported in large-
3438
CANCER
December 15, 2008 / Volume 113 / Number 12
cohort studies investigating the effects of surgical
resection on VO2peak.4,5 These findings suggest that
our sample may be representative of a wider population of postoperative NSCLC patients. Finally, the
main purpose of this study was to examine the feasibility and preliminary efficacy of aerobic training in
this setting.
Another noteworthy limitation is that beneficial
changes in VO2peak may be explained by the natural
history of postoperative recovery. To minimize this
issue, patients were recruited at least 3 weeks postresection (mean, 30 3 days). Nevertheless, the time
course of postsurgical ‘natural’ recovery in VO2peak
has not been well characterized. Therefore, it is
entirely possible that our observed findings may be
partially explained by this phenomenon. Withstanding
the significant selection bias and spontaneous postoperative recovery, we believe the present findings
provide strong promising evidence for further investigation of exercise training in operable lung cancer.
In conclusion, this pilot study provided proof of
principle that supervised aerobic training may be
safe and feasible for select postsurgical NSCLC
patients. Aerobic exercise training is also associated
with significant improvements in QOL and select cardiopulmonary endpoints, particularly among patients
not receiving systemic therapy. Larger randomized
trials are now warranted.
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