phd thesis perioperative rehabilitation in operable lung ... · therapies 2016;1-12 iii. sommer ms,...
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U N I V E R S I T Y O F C O P E N H A G E N
F A C U L T Y O R D E P A R T M E N T
PhD Thesis
Maja Schick Sommer, MHS, physiotherapist
Supervisors: Henning Langberg, Jesper Holst Pedersen, Klaus Richter Larsen
Submitted to the Graduate School of Health and Medical Sciences, University of
Copenhagen December 30, 2017
Perioperative Rehabilitation in Operable Lung
Cancer Patients (PROLUCA)
2
Department: Department of Public Health, Section of Social Medicine, University of
Copenhagen
Author: Maja Schick Sommer, MHS, physiotherapist
Title and subtitle: Perioperative Rehabilitation in Operable Lung Cancer Patients
(PROLUCA)
Submitted: December 30, 2017
Academic advisors:
Associate Professor Jesper Holst Pedersen
Department of Cardiothoracic Surgery RT 2152 Rigshospitalet
University of Copenhagen, Copenhagen, Denmark
Associate Professor Klaus Richter Larsen
Department of Respiratory Medicine, Bispebjerg University Hospital
University of Copenhagen, Copenhagen, Denmark
Professor Henning Langberg
Faculty of Health and Medical Sciences, Department of Public Health, Section of Epidemiology,
CopenRehab
University of Copenhagen, Copenhagen, Denmark
Members of the assessment committee:
Professor Peter Lange
Department of public health, Faculty of Health, Section of Social Medicine
University of Copenhagen, Copenhagen, Denmark
Professor Jan Jesper Andreasen
Department of Clinical Medicine, Aalborg University Hospital
Aalborg University, Aalborg, Denmark
PhD Researcher Lene Thorsen
National Resource Center for Late Effects, Department of Oncology,
Oslo University Hospital and University of Oslo, Oslo, Norway
3
Table of contents
PREFACE AND ACKNOWLEDGEMENTS ......................................................................... 7
LIST OF PAPERS ............................................................................................................... 8
ARTICLES AT A GLANCE ................................................................................................. 9
ABBREVIATIONS ............................................................................................................. 10
DANSK RESUMÉ .............................................................................................................. 12
ENGLISH SUMMARY ....................................................................................................... 14
BACKGROUND ................................................................................................................ 16
Lung Cancer .................................................................................................................................................................... 16
Incidence and Prognosis .............................................................................................................................................. 16
Staging and Treatment Modalities ............................................................................................................................... 17
Operable Lung Cancer ................................................................................................................................................... 18
Surgical Procedure and Postoperative Complications.................................................................................................. 18
Physical and Mental Impact of Surgery ....................................................................................................................... 18
Exercise and Surgery in Lung Cancer .......................................................................................................................... 19
Preoperative Evaluation and Exercise .......................................................................................................................... 19
Postoperative Exercise ................................................................................................................................................. 20
Theoretical Framework .................................................................................................................................................. 21
Organizational Context .................................................................................................................................................. 22
OBJECTIVES .................................................................................................................... 23
Hypotheses ....................................................................................................................................................................... 24
METHODS AND MATERIALS .......................................................................................... 24
Structure of the PROLUCA Project ............................................................................................................................. 24
Methods (Paper II-III) ................................................................................................................................................... 25
Recruitment and Eligibility .......................................................................................................................................... 25
4
Group Allocation (randomization) ............................................................................................................................... 26
Interventions ................................................................................................................................................................ 26
Outcome Measures (Paper II-III).................................................................................................................................. 27
Safety and Adherence .................................................................................................................................................. 28
Cardiorespiratory Capacity .......................................................................................................................................... 29
Muscular Strength ........................................................................................................................................................ 29
Walking Distance ......................................................................................................................................................... 30
Pulmonary Capacity ..................................................................................................................................................... 30
Patient-Reported Outcome Measures ........................................................................................................................... 30
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Cancer 30 (EORTC
QLQ-C30) / Lung Cancer 15 (EORTC QLQ-LC15) ................................................................................................... 30
Functional Assessment of Cancer Therapy–Lung (FACT-L) questionnaire ................................................................ 31
36-item Short Form Health Survey (SF-36) ................................................................................................................. 31
Hospital Anxiety and Depression Scale (HADS) ........................................................................................................ 32
The National Comprehensive Cancer Network (NCCN) Distress Thermometer ........................................................ 32
Multidimensional Scale of Perceived Social Support (MSPSS) .................................................................................. 32
Preoperative Exercise Training Protocol (Paper II-III) .............................................................................................. 32
Postoperative Exercise Training Protocol (Paper II-III) ............................................................................................ 33
Methods and Materials in the Systematic Review (Paper IV) .................................................................................... 34
Search Strategy ............................................................................................................................................................ 34
Inclusion Criteria and Data Extraction ......................................................................................................................... 35
Risk of Bias and Quality of Evidence Assessment ...................................................................................................... 36
STATISTICAL CONSIDERATIONS .................................................................................. 37
Data Analysis in the Feasibility Study (Paper II-III) ................................................................................................... 37
Statistical Analyses in the Systematic Review (Paper IV) ........................................................................................... 38
Sensitivity Analysis ..................................................................................................................................................... 39
ETHICAL CONSIDERATIONS .......................................................................................... 39
RESULTS FROM THE FEASIBILITY STUDY (PAPER II-III) ............................................ 39
Patient Characteristics and Recruitment ..................................................................................................................... 39
Safety ............................................................................................................................................................................... 43
5
Postoperative Complications, Recurrence, and Mortality .......................................................................................... 43
Dropouts .......................................................................................................................................................................... 44
Adherence to Home-based Preoperative Exercise ....................................................................................................... 44
Adherence to Supervised Postoperative Group Exercise ............................................................................................ 45
Changes in Physiological Capacity ................................................................................................................................ 46
Changes in HRQoL......................................................................................................................................................... 47
Changes in Smoking, Alcohol, and Physical Activity Habits ...................................................................................... 48
RESULTS FROM THE SYSTEMATIC REVIEW (PAPER IV) ........................................... 48
Risk of Bias ...................................................................................................................................................................... 51
Effect of Intervention ..................................................................................................................................................... 51
DISCUSSION .................................................................................................................... 53
Summary of Main Findings ........................................................................................................................................... 53
Safety ............................................................................................................................................................................... 54
Postoperative Complications ......................................................................................................................................... 56
Recruitment ..................................................................................................................................................................... 57
Adherence to the Preoperative Exercise ....................................................................................................................... 57
Adherence to Postoperative Exercise ............................................................................................................................ 58
Cardiorespiratory Capacity ........................................................................................................................................... 59
Muscle Strength .............................................................................................................................................................. 60
Walking Distance ............................................................................................................................................................ 61
HRQoL Outcomes .......................................................................................................................................................... 62
Changes in Smoking, Alcohol and Physical Activity Habits ....................................................................................... 63
Effect of Early Postoperative Exercise .......................................................................................................................... 64
6
Methodological Considerations ..................................................................................................................................... 65
Strengths and Limitations .............................................................................................................................................. 66
CONCLUSION ................................................................................................................... 67
PERSPECTIVES ............................................................................................................... 67
REFERENCES .................................................................................................................. 69
APPENDICES ................................................................................................................... 85
7
Preface and Acknowledgements
This thesis was initiated because Copenhagen Centre for Cancer and Health has a profound
ongoing interest in investigating and developing the best rehabilitation for cancer patients. This
interest in improving standard practice has led to national and international collaboration with
various research departments. The present research project, PROLUCA, received grants from the
Center for Integrated Rehabilitation of Cancer Patients (CIRE), which was established and is
supported by the Danish Cancer Society and the Novo Nordisk Foundation. Financial support
has also been provided by the City of Copenhagen, Rigshospitalet and the Faculty of Health and
Medical Sciences, University of Copenhagen.
First, I would particularly like to thank the patients who participated in the PROLUCA feasibility
study for their bravery and willingness to be the first group to begin exercising two weeks after
lung cancer surgery. I would also like to express my most sincere gratitude to everyone who
contributed to this thesis because clinical research requires an immense amount of effort and I
could not have gotten this far on my own. I also owe a debt of appreciation to the staff at
Copenhagen Centre for Cancer and Health for their superb help, huge flexibility and excellent
cooperation in collecting data, but also to the outstanding staff at the collaborating hospitals for
their contribution to the data collection.
This thesis would not have been possible without the tremendous support of my boss and head of
Copenhagen Centre for Cancer and Health, Jette Vibe-Petersen, and research coordinator and
nurse Karen Trier. A heartfelt thank you to both of you for the time and effort you invested in
this thesis. I also wish to give a special thanks to my supervisors Jesper Holst Pedersen, Klaus
Richter Larsen and Henning Langberg for providing me with competent academic feedback. I
also want to thank my colleagues at Copenhagen Centre for Cancer and Health, CopenRehab and
CIRE research group for their great support and invaluable help.
Finally, my deepest gratitude goes to my family and friends for their incredible support.
Maja Schick Sommer
Copenhagen, December 2017
8
List of Papers
I. Sommer MS, Trier K, Vibe-Petersen J, Missel M, Merete C, Larsen KR, Langer SW,
Hendriksen C, Clementsen P, Pedersen JH, Langberg H. Perioperative rehabilitation
in operation for lung cancer (PROLUCA): Rationale and design. BMC Cancer 2014;
14:404
II. Sommer MS, Trier K, Vibe-Petersen J, Missel M, Merete C, Larsen KR, Langer SW,
Hendriksen C, Clementsen P, Pedersen JH, Langberg H. Perioperative rehabilitation
in operable lung cancer patients (PROLUCA): A feasibility study. Integrative Cancer
Therapies 2016;1-12
III. Sommer MS, Trier K, Vibe-Petersen J, Christensen KB, Missel M, Merete C, Larsen
KR, Langer SW, Hendriksen C, Clementsen P, Pedersen JH, Langberg H. Changes in
health-related quality of life during rehabilitation in patients with operable lung
cancer: A feasibility study (PROLUCA). Integrative Cancer Therapies 2016;1-13
IV. Sommer MS and Staerkind MEB, Christensen J, Vibe-Petersen J, Larsen KR,
Pedersen JH, Langberg H. The effect of postsurgical rehabilitation programmes in
patients operated for lung cancer: A systematic review and meta-analysis. Journal of
Rehabilitation Medicine 2017; accepted for publication
9
Articles at a Glance
Aim Methods and Materials Results Conclusion
Pa
per
I
(Co
nce
pt
pa
per
)
To present the design
of the PROLUCA
RCT PERI in order
to identify the
optimal timing of
exercise to improve
VO2peak in
postoperative
NSCLC patients
A 2x2 factorial design
with continuous effect
endpoint (VO2peak);
380 patients with
NSCLC randomized
to four exercise
groups
Due to a low recruitment
rate this RCT study was
changed into a feasibility
study
The low recruitment rate
made it unrealistic to
finish the study within
the planned time frame
and therefore the study
design was adjusted.
Pa
per
II
To investigate the
safety and feasibility
of a preoperative and
early postoperative
rehabilitation
program in patients
operated for NSCLC
Forty patients with
operable NSCLC
randomized to a
combination of
preoperative home-based
exercise and a
postoperative
rehabilitation program.
Study endpoints were
inclusion rate, adherence,
and number of adverse
events
The postoperative exercise
was completed by 73% of
the patients randomized to
this intervention. No
adverse events were
observed. The preoperative
home-based exercise
program was not feasible
due to interfering
diagnostic procedures and
fast-track surgery
The early postoperative
exercise program for
patients with NSCLC
was safe and feasible,
but in a fast-track set up,
a preoperative home-
based exercise program
was not feasible for this
population
Pa
per
III
To present HRQoL
changes over time
before and one year
after surgery in
patients with NSCLC
participating in a
rehabilitation
program.
Same sample as in Paper
II. Study endpoints were
self-reported HRQoL,
distress, anxiety,
depression and social
support
Emotional well-being,
global QoL and mental
health component score
(P=0.0004) showed an
overall statistically
significant improvement
during the study period.
There was also a reduction
in distress, anxiety,
smoking and alcohol habits
HRQoL improved
significantly and a
reduction in distress,
anxiety, smoking and
alcohol habits was also
found during the study
from time of diagnosis
until one year after
resection in patients
with NSCLC
participating in
rehabilitation
Pa
per
IV
To systematically
search and review
the evidence of early
postoperative
exercise in patients
with lung cancer
Five databases were
searched systematically
for RCTs assessing the
effects of postoperative
exercise interventions in
patients following lung
resection for NSCLC
The literature search
identified 6191 hits and
four studies were included.
Exercise capacity and
HRQoL were found to be
significantly higher in the
intervention group
compared with the control
group. There was no
difference between the
effect of late and early-
initiated exercise
interventions
Exercise has a small to
moderate effect on
exercise capacity and
the physical component
of HRQoL. Early-
initiated exercise
programs did not show
an effect on exercise
capacity. Findings
should be interpreted
with caution
10
Abbreviations
ACSM American College of Sports Medicine
ATS American Thoracic Society
BP Blood Pressure
CI Confidence Interval
CONSORT Consolidated Standards of Reporting Trials
COPD Chronic Obstructive Pulmonary Disease
DHA Danish Health Authority
DM Diabetes Mellitus
EORTC QLQ-C30 European Organization for Research and Treatment of Cancer Quality
of Life Questionnaire Cancer 30
EORTC QLQ-LC13 European Organization for Research and Treatment of Cancer Quality
of Life Questionnaire Lung Cancer 15
FACT-L Functional Assessment of Cancer Therapy-Lung
FEV1 Forced Expiratory Volume in the first second
FVC Forced Vital Capacity
GRADE Grading of Recommendations, Assessment, Development and
Evaluation
HADS Hospital Anxiety and Depression Scale
HR Heart Rate
HRmax Maximal Heart Rate
HRQoL Health-Related Quality of Life
LCS Lung Cancer Subscale
MID Minimal Important Difference
MSPSS Multidimensional Scale of Perceived Social Support
n Number
NCCN National Comprehensive Cancer Network
NSCLC Non-small Cell Lung Cancer
PROLUCA Perioperative Rehabilitation in Operable LUng CAncer patients
QoL Quality of Life
r Correlation coefficients
11
RCT Randomized Clinical Trial
SD Standard Deviations
SF-36 Short Form Health Survey
SMD Standardised Mean Differences
TNM Tumor Node Metastasis
VATS Video-Assisted Thoracoscopic Surgery
VO2max Volume of maximal oxygen consumption
VO2peak Volume of peak oxygen consumption
WHO World Health Organization
1RM 1 Repetition Maximum
6MWD Six-Minute Walk Distance
12
Dansk resumé
Titel: Perioperativ Rehabilitering ved Operation for LUngeCAncer (PROLUCA)
Baggrund: En forbedret overlevelse for patienter med operable lungekræft har betydet, at flere lever
længere med fysiske og psykosociale følger til sygdom og behandling. Følger som nedsat fysisk
kapacitet, træthed og depression kan nedsætte patientens funktionsevne og livskvalitet. Forskning
tyder på, at fysisk træning i forbindelse med behandling af en række kræftsygdomme, herunder
operabel lungekræft, har en positiv effekt på såvel fysiske som psykologiske parametre. Få
undersøgelser beskæftiger sig med en tidlig indsats. Forskning har ikke tidligere belyst sikkerheden
og gennemførbarheden af en perioperativ rehabiliteringsindsats, i kommunale omgivelser, hvor den
postoperative træning består af høj intensivt interval træning, der initieres 2 uger efter en operation
for lungekræft.
Formål: Det overordnede mål med denne ph.d. afhandling var at evaluere sikkerheden og
gennemførbarheden af en perioperativ rehabiliterings indsats i kommunale omgivelser, bestående af
præoperativ fysisk træning og tidlig postoperativ rehabilitering, med fokus på træning, i forbindelse
med helbredende operation for lungekræft. I tillæg undersøger denne afhandling effekten af tidlig
postoperativ træning sammenlignet med sen iværksat træning til samme patient population.
Metode: Afhandlingen består af en undersøgelse af sikkerhed og gennemførbarhed i et klinisk
lodtrækningsforsøg, hvor 40 deltagerne afprøvede en af fire interventioner, heraf tre
eksperimentelle og én kontrol (artikel I-III). I tillæg blev en systematisk gennemgang af litteraturen
og en metaanalyse anvendt til at belyse effekten af tidlig postoperativtræning til patienter med ikke
småcellet lungekræft (artikel IV).
Resultater:
Ingen utilsigtede hændelser opstod under den tidlige postoperative træning og gennemsnitligt
startede patienterne randomiseret til den tidlige iværksatte træningsgruppe 18 dage efter operation
(range 13-29) og 47 dage (range 22-80) efter operation i den sent iværksatte træningsgruppe. Ingen
patienter havde spontane eller uventede reaktioner til at træne høj intensivt interval træning to uger
efter operationen. Den postoperative træning blev gennemført af 73% af de patienter der var
randomiseret til denne intervention. Da kun tre patienter ud af tolv trænede dagligt før operationen i
13
et accelereret patient forløb blev den præoperative hjemmetræning vurderet ikke gennemførbar, da
der ofte er diagnostiske tiltag som tager tid og kræfter hos patienterne kombineret med det
accelererede patient forløb som maksimalt efterlader 2 uger fra diagnose til operation.
I det systematiske review blev fire randomiserede kontrollerede forsøg identificeret, omhandlende
262 deltagere. Resultater ved kort opfølgning (12-20 uger) viste signifikant højere fysisk kapacitet
og den fysiske komponent af den helbredsrelaterede livskvalitet i interventionsgruppen
sammenlignet med kontrol gruppen; henholdsvis standardiseret gennemsnits forskel på 0.47 (95%
konfidens interval 0.07 til 0.88) og standardiseret gennemsnits forskel på 0.51 (95% CI 0.22 til
0.80). Ingen effekter var at se på den fysisk kapacitet eller den helbredsrelaterede livskvalitet i en
sensitivitets analyse af det studie som initierede træning tidligt, indenfor to uger postoperativt.
Konklusion:
Denne afhandling fandt at høj intensivt interval træning, der er iværksat 2 uger efter operation for
ikke små-cellet lungekræft er sikkert og gennemførbart i en kommunal setting. Rekrutteringen af
patienter med ikke små-cellet lungekræft til perioperativ rehabilitering med fokus på træning var
udfordrende i et accelereret patient forløb. Den præoperative hjemmetræning var inkonsekvent og
ikke gennemførbar i et set-up, hvor der maksimalt er 14 dage mellem diagnose og operation (artikel
II-III). Det systematiske review fandt, at træning kan have gavnlige effekter på trænings kapacitet
samt den fysiske og mentale komponent af HRQoL for operable lungekræft patienter. Grundet lav
kvalitet af evidensen må disse resultater tolkes med forsigtighed. Det var ikke muligt at konkludere
på effekten af tidlig postoperativ træning sammenlignet med en sent iværksat træning på grund af
mangel på veludførte randomiserede kontrollerede forsøg (artikel IV).
14
English Summary
Background: Lung cancer is the leading cause of cancer-related death worldwide. The most
effective treatment in early stages of non-small cell lung cancer (NSCLC) is at present lung
resection. Despite improvements in medical and surgical treatment of NSCLC, surgery is
associated with a potentially substantial morbidity, functional limitations and decreased health-
related quality of life (HRQoL). Patients with NSCLC are typically older and are current or
former smokers, and they commonly have other concomitant smoking related chronic diseases
(e.g., COPD, ischemic heart disease) that may affect the cardiorespiratory system. Literature on
NSCLC patients indicates that exercise is beneficial, but research is limited, highlighting that
supporting evidence is needed to determine the optimal type, timing and amount of exercise
when diagnosed with lung cancer.
Aim: The overall aim of this thesis was to evaluate the safety and feasibility of preoperative and
early postoperative non-hospital rehabilitation, with a focus on exercise, in patients with
NSCLC. Subsequently, it was also to evaluate, in a systematic review, the effect of early-
initiated postoperative exercise compared to late-initiated exercise in the same population.
Methods: Different research designs were applied in this PhD thesis. Paper I describes the setup
of the PROLUCA RCT I. Papers II-III examine a single-centre four-arm prospective randomized
controlled feasibility study in 40 patients with operable lung cancer. Paper IV is a comprehensive
systematic review and meta-analysis of the available evidence from randomized controlled trial
(RCT) comparable studies.
Results: No adverse events were reported or observed during the postoperative exercise program,
and the average onset of exercise was 18 days (range 13-29) post surgery in the early
intervention group and 47 days (range 22-80) in the late intervention group. No patients had
spontaneous or unexpected reactions to performing high intensity interval exercises two weeks
after surgery and the postoperative exercise was completed by 73% of the patients randomized to
this intervention. Three out of 12 patients managed to exercise daily prior to surgery in a fast-
track setting, which is why the preoperative home-based exercise program was interpreted as not
feasible due to interfering diagnostic procedures and the fast-track surgery, which only left one
to two weeks between diagnosis and surgery. Four RCTs were identified involving 262
15
participants. Results on short-term follow-up (12-20 weeks) showed a significantly higher
exercise capacity and physical component of HRQoL in the intervention group compared to the
control group, standardised mean difference (SMD) 0.47 (95% confidence interval (CI) 0.07 to
0.88) and SMD 0.51 (95% CI 0.22 to 0.80), respectively. No short-term effects were seen on any
of these outcomes in a sensitivity analysis of studies initiating exercise training early, i.e., within
two weeks post surgery.
Conclusion: This thesis showed that a high intensity interval exercise program starting two
weeks after surgery in patients with NSCLC was safe and feasible. Recruitment of NSCLC
patients to the perioperative rehabilitation intervention, with a focus on exercise, was challenging
in a fast-track surgical program. The preoperative home-based exercise was found to be
inconsistent and not feasible in a set-up where the time interval between referral and surgery
(fast-track surgical program) was restricted to 14 days (Paper II-III). This thesis also showed, in
a systematic review, that exercise improved exercise capacity and the physical component of
HRQoL in the short-term, but no beneficial effect was found in the mental component of
HRQoL. In the systematic review, it was not possible to draw conclusions about the effect of
early-initiated postoperative exercise compared to late-initiated exercise due to the lack of well-
conducted RCTs.
16
Background
Lung Cancer
Incidence and Prognosis
Lung cancer is a leading cause of cancer-related death worldwide and the most common cancer
(1). Global lung cancer incidence rates continue to decline, but gender differences exist
nationally and internationally, with women facing a growing risk and men a falling risk (1,2). In
Denmark, more than 4500 patients are diagnosed with lung cancer every year (3,4). Due to its
high mortality, the disease accounts for 24% of all cancer-related deaths, which is comparable to
the estimated 26% of all cancer-related deaths in the United States of America (2,5).
At the close of 2015, the number of people living with or after lung cancer in the Nordic
countries was 33236, of whom 10435 were Danes (5). At present, the international median age at
diagnosis is more than 70 years, which is comparable to the situation in Denmark (4,6).
Although lung cancer does occur in people under the age of 55, it is uncommon (6). The gender
differences mentioned above are caused by historical differences in tobacco use, which is why
slightly more men (54%) than women (46%) are diagnosed with lung cancer. Women took up
smoking in large numbers later, at an older age than men and women are slower to quit smoking
(2,4).
Cigarette smoking, the greatest risk factor for lung cancer, is estimated to be responsible for 90%
of all cases. Another known risk factor for lung cancer includes exposure to various occupational
and environmental carcinogens (7). Consequently, tobacco-related diseases are particularly
frequent in patients with lung cancer (8,9). Comorbidity affects the outcome of patients with
lung cancer in several ways, such as decreased performance status, reducing the efficacy of the
treatment and increasing the side effects (10). As a prognostic factor, comorbidity is a part of the
risk stratification in patients who are candidates for the treatment of lung cancer. Out of the four
most common cancer diagnoses, patients with lung cancer have the highest prevalence of
comorbidities, with the most prevalent comorbidity being chronic obstructive pulmonary disease
(COPD). In an American population-based study with 6000 patients diagnosed with lung cancer,
COPD was present in around 53% of them, diabetes mellitus (DM) in 16% and congestive heart
failure in 13% (11,12). Other comorbidities, such as, hypertension, ischemic heart disease and
17
cerebrovascular disease are also present in patients diagnosed with lung cancer (9). These
comorbid diseases are considered to have a significant influence on the survival rate of lung
cancer patients (13). Furthermore, previous studies have demonstrated that less aggressive
treatment is given to patients with lung cancer with specific existing comorbidities (14). In
Denmark, half of the patients diagnosed with lung cancer have one or more comorbidities at the
time of diagnosis (4), which is comparable to studies from other European countries (9,15).
Besides comorbidity, age and performance status, the prognosis of patients with lung cancer is
affected by the anatomic extent of the lung cancer disease (16). In Denmark, the five-year
survival rate is around 50% in patients with lung cancer stage IA, whereas a very poor prognosis
is found in patients with lung cancer classified as stage IV, 2% of whom are alive five years after
time of diagnosis (17). These numbers are comparable to international prognoses (18). In
general, the prognosis of lung cancer patients is also affected by environment-related factors,
such as access and quality of care, and treatment-related factors, e.g., the type of treatment
selected and the initiation of treatment (16).
Staging and Treatment Modalities
Lung cancer is classified into two major histologic types: non-small cell lung cancer (NSCLC)
and small cell lung cancer (SCLC) (19). NSCLC, the most common type worldwide, accounts
for approximately 85% of all new lung cancer diagnoses (4,20). Adenocarcinoma, squamous cell
carcinoma and large cell carcinoma are the three main NSCLC subtypes (21). The extent of the
disease is classified by the Tumor Node Metastasis (TNM) system, version seven (22), which is
used to select candidates for surgical resection (22,23). Patients classified as stage one, two and
partly three (stage I, II, IIIA), are candidates for lung resection (22,23). In Europe, the proportion
of patients who undergo surgery for lung cancer is around 10-20% (24). In Demark,
approximately 30% of patients diagnosed with lung cancer are suitable for treatment with
curative intention (4), with around 20% receiving surgical treatment and 10% undergoing
radiotherapy treatment (4). Adjuvant chemotherapy is offered in approximately one third of the
patients following lung resection, whereas radiotherapy is rarely used as an adjuvant to surgery
(4,25). The selection of patients who are offered adjuvant chemotherapy is based on TNM
staging, histology, comorbidity and general condition. Treatment of patients with inoperable
lung cancer, stage IIIb and IV, is life-prolonging and symptom relieving (22).
18
Operable Lung Cancer
Earlier detection of lung cancer and improvements in surgical techniques, combined with more
effective adjuvant treatments, has led to improved survival for patients with operable lung cancer
(25). Today, the two and five-year survival rate in Denmark is 79% and 56%, respectively,
following surgery for lung cancer (17). In Denmark, the overall risk of mortality 30 days after
surgery is 1%, which is in accordance with the findings in a survey from the U.S. conducted in
2002-2008 (4,26), but lower than the 2.6 % reported from the UK (27).
Surgical Procedure and Postoperative Complications
The surgical procedure consists of removal of the affected lung tissue, combined with removal of
the regional (mediastinal or peribronchial) lymph nodes (28). The degree of resection ranges
from wedge resection or segmentectory to major resections with removal of one or two lobes
(lobectomy or bilobectomy) or pneumonectomy (29). The surgical approach is either by
thoracotomy (open method) or minimal invasive video-assisted thoracoscopic surgery (VATS)
(19,25). The proportion of NSCLC patients treated with VATS nationally is 66% but has
regional variations, with the highest number (86%) at Copenhagen University Hospital,
Rigshospitalet (17). The VATS approach allows earlier recovery, with fewer postoperative
complications (30) and shorter hospital stays (31,32). Postoperative complications are defined as
complications occurring within 30 days after surgery (33). The rate of complications after
thoracic surgery varies between 19 to 59% (34) and, in Denmark, 25% of patients treated for
NSCLC experience one or more postoperative complications (17). The most common
postoperative complication is prolonged air leakage (9%), pneumonia (5%) and cardiac
arrhythmias (3%) (17,35).
Physical and Mental Impact of Surgery
Despite improvements in the treatment modalities of NSCLC, surgery, in addition to
postoperative complications, is also associated with long-term and late effects of the surgery.
Long-term effects are defined as side effects or complications that begin during or very shortly
after treatment and persist afterward, causing compensatory behavior in patients with cancer.
Late effects distinguish themselves from long-term effects in that they appear months or years
after treatment completion (e.g., arrhythmias or cardiomyopathies after exposure to cardiotoxic
agents) (36). Long-term and late side effects following surgery for NSCLC are a reduction of
pulmonary capacity, cardiorespiratory capacity and decreased quality of life (QoL) (31,32).
19
Depending on the extent of the resection, both pulmonary and exercise capacity are decreased
just after surgery and followed by an increase during the first 12 months, leading to a permanent
loss in pulmonary capacity of around 10-15% (32,33,37) and a 16% loss in exercise capacity six
month after surgery (38). A decrease in post-surgical pulmonary capacity measured by forced
expiratory volume in the first second (FEV1) and health-related quality of life (HRQoL)
compared to pre-surgical status has been demonstrated in individuals with NSCLC, up to two
years after surgery (39,40). Compared to healthy individuals, the levels of exercise capacity and
HRQoL are significantly impaired after lung resection in patients with NSCLC (41).
Exercise and Surgery in Lung Cancer
Exercise is defined as physical activity that is planned, structured and repetitive, with the goal to
obtain or maintain physical fitness (42). Several systematic reviews and meta-analyses have
extensively evaluated the literature investigating the effect of exercise following a cancer
diagnosis. All of them come to the same conclusion, that exercise training is beneficial both
during and following the completion of adjuvant therapy in adult cancer patients (43–48).
Evidence on the beneficial effect of exercise has been established for relatively few cancer
diagnoses and research in this area is primarily conducted in patients with breast and colon
cancer (43–48). Research on exercise in lung cancer has previously been given low priority,
partly due to the low survival rate. In the last 10-15 years, the amount of research evaluating
exercise interventions for patients with lung cancer has grown (49,50).
Preoperative Evaluation and Exercise
Danish and international clinical practice guidelines recommend that all patients undergo
preoperative assessment of the risks of surgery (17,25). In Denmark, this risk assessment
includes the following: 1) assessment of lung function, which entails: spirometry and measuring
the lung carbon monoxide transfer factor, regardless of spirometric values; 2) calculation of the
predicted postoperative lung function (using ventilation scintigraphy, perfusion scintigraphy or
quantitative computed tomography (CT) scan; and 3) general functional assessment using either
a six-minute walk distance (6MWD) test (a distance of >400 meter is a cut-off for good function)
or a cardiorespiratory exercise test to measure volume of peak oxygen consumption (VO2peak)
(using >15 mlO2/kg/min as a cut-off for good function) (25). The guidelines use the term
“consider” for the assessment of functional capacity (25), and due to restricted availability, these
tests are not used routinely in assessing the risk of surgery. When maximal oxygen consumption
20
(VO2max) is <10mL/kg/min, patients are potentially at high risk of serious postoperative
complications, which is why lobectomy and pneumonectomy are usually not recommended (51).
In addition, international guidelines also recommend: assessment for operative mortality using a
global risk score, such as a thoracoscore to estimate the risk of death and a risk assessment for
cardiovascular morbidity using the American College of Cardiology guidelines as a basis for
assessing perioperative cardiovascular risk (25).
For patients assessed as unfit for surgery, the prognosis changes dramatically since the treatment
for lung cancer is no longer curative but palliative (52). Preoperative exercise offered to NSCLC
patients attracts attention because it may move patients from being unfit for surgery to being fit
for surgery, consequently changing the prognosis of these patients dramatically (53). Preliminary
evidence suggests that higher exercise capacity at the time of a diagnosis of NSCLC is related to
prolonged survival (43,54). A recent Cochrane meta-analysis found that compared to no exercise
training, preoperative exercise training showed a 67% reduction in the risk of developing
postoperative pulmonary complications risk ratio (RR) 0.33, 95% confidence interval (CI) 0.17
to 0.61). This meta-analysis found that preoperative exercise decreased the duration of
intercostal catheter use and postoperative length of hospital stay but also that exercise capacity
and lung capacity, expressed as 6MWD and forced vital capacity (FVC), improved in people
undergoing lung resection (53). Previous studies have demonstrated lower levels of exercise
behavior among patients diagnosed with NSCLC compared to healthy individuals at the time of
diagnosis, which supports the need for a preoperative exercise intervention (55).
Postoperative Exercise
Resection of the lung immediately affects cardiorespiratory capacity since lung tissue is
removed, reducing the ventilatory and diffusion capacity (56). Furthermore, the cardiorespiratory
capacity is affected negatively due to prolonged periods of bed rest, pain and inactivity (57). The
level of physical activity is found to be lower from time of diagnosis and during the first six
months following a diagnosis of NSCLC compared to healthy age-matched controls (55).
Caspersen et al (1985) define physical activity as: “…a bodily movement by skeletal muscles
that results in energy expenditure” (42). Additionally, there is an age-related limitation to
exercise since cardiorespiratory capacity declines by around 10% per decade in healthy adults
(58,59). Also, comorbidity adversely affects cardiorespiratory capacity and contributes to the
aging effects (60). Evidence shows that postoperative exercise for NSCLC patients is both safe
and associated with improvement in cardiorespiratory capacity and self-reported outcomes, such
21
as HRQoL and fatigue (49,61). Still, more research is required to understand the potential effect
of exercise on NSCLC patients and to determine how individual components such as mode,
intensity, frequency, duration and timing may contribute to the effect (49). In addition, patients
who are offered adjuvant chemotherapy after surgery for lung cancer are even more exposed to
deconditioning since chemotherapy is associated with an acute and long-term impact on the
cardiovascular system (62). The direct effects of NSCLC chemotherapeutics on cardiopulmonary
function in combination with lung surgery are not fully understood, although platinum-based
regimens are found to reduce FEV1 and cause anemia in patients with advanced lung cancer,
affecting the physiologic adaptations to exercise (63). Research on the effect of exercise in
patients with operable lung cancer receiving chemotherapeutics is diverse. One 2008 study
indicated greater improvements in cardiopulmonary capacity and HRQoL endpoints among
patients not receiving adjuvant chemotherapy (64). Another study showed an increase in median
peak oxygen uptake of 2.6 mL/kg/min (range –0.9 to 3.9) in the exercise group compared to a
decrease of 0.4 mL/kg/min (range –7.9 to 10.2) in the control group. The same study also found
that none of the patients receiving chemotherapy were able to exercise during the last course of
adjuvant chemotherapy, but seven out of nine patients successfully continued exercising
subsequently (65). For an exercise intervention to be successful, it is important that the cancer
patients adhere to the exercise program, but adherence during and after cancer treatment has
previously been reported as challenging (66). Cyarto et al (2006) define adherence as: “… the
degree of attendance or completion of prescribed exercise sessions” (67). A low adherence rate
could also reflect the applicability of the exercise intervention in daily practice (68).
Theoretical Framework
The theoretical framework of the present thesis is inspired by the multiple-hit hypothesis and a
concept called oxygen cascade, described by Lee Jones in 2007 and 2009 respectively (60,69).
The multiple-hit hypothesis, a schematic presentation of cancer patients and their progress
through the selected treatment regimens, highlights the fact that cancer and the treatment of
cancer will have a negative impact on the patient’s cardiovascular system and increase the risk of
cardiovascular disease dramatically (69). Oxygen cascade describes the negative reaction to the
treatment of cancer that affects the functional capacity of cancer patients (50). Another
theoretical framework is a concept called the teachable moment, a term used to describe the
transition that takes place when patients are diagnosed with cancer (53). This transition can
modify barriers and motivate the patient. Notably, the time of diagnosis has previously proven to
22
be an important health event that can also modify barriers and motivate patients to adopt a
healthier lifestyle (70), possibly serving to improve participation in perioperative rehabilitation.
The timing of initiating exercise may also influence outcomes in patients resected for NSCLC.
Organizational Context
Figure 1 presents the rehabilitation services at the municipal rehabilitation centre in Copenhagen.
Of these interdisciplinary interventions available, exercise is to date the most well documented
as being beneficial for a variety of cancer patients, including patients with lung cancer
(48,49,71). However, there are still many unknown questions regarding the optimal exercise
program for patients with different cancer diagnoses and the influence of comorbidity (61). The
Danish Health Authority (DHA) has emphasized the need to clarify which exercise interventions
should be offered to patients with different cancer diagnoses and the timing of the exercise
interventions in the treatment trajectory (72,73).
Figure 1. Municipal rehabilitation for patients with cancer at the Copenhagen Centre for Cancer and Health
In order to ensure that exercise and rehabilitation guidelines for cancer patients are applicable to
daily practice, it is important that the research is carried out in close collaboration with the clinic
Diagnosis Follow-up
Cancer patients´ course of disease
Cancer treatment
Contact person
A physiotherapist,
nurse, or dietician
is assigned to
each patient
throughout the
program
Assessment interview
An individualized
rehabilitation program is
planned jointly by the patient
and contact person
Last follow-up
interview
Focus on completion
of program
Referral Completion
Rehabilitation program at Copenhagen Centre for Cancer and Health
Multidisciplinary intervention programAssessment
Physical activity
Strength and cardiovascular training, stability
training, nature activities, running teams
Dietary guidance
Individual and group counseling, cooking
Social counseling
Individual counseling, rights, return to work
Patient education
Disease/medication, life-style issues, coping
skills, experience sharing
Other options
Smoking cessation, meetings for relatives,
counseling, yoga and mindfulness provided by
the Danish Cancer Society
MUNICIPAL REHABILITATION FOR PATIENTS WITH CANCER
Completion
interview
Focus on adherence
to changed life style
Rehabilitation needs
based on screening for:
•Physical activity
•Smoking
•Diet
•Alcohol
•Disease and treatment
specific symptoms
•Social, existential and
psychological challenges
•Relatives
•Network
•Sexuality
•Sleep
•Stress
23
and, preferably, in the clinical setting (74). Research in a clinical setting can be challenging since
it may include a great deal of coordination between various sectors (75). Figure 2, which
presents a summary of the collaborating departments and their role in the treatment trajectory of
NSCLC patients, illustrates the complexity of the PROLUCA research project.
Figure 2. Organizational context
Objectives
The overall aim of this thesis was to evaluate the safety and feasibility of preoperative and early
postoperative non-hospital rehabilitation, with focus on exercise in patients with NSCLC.
Subsequently, the aim was also to evaluate the effect of early-initiated postoperative exercise
compared to late-initiated exercise in the same population.
Mu
nic
ipa
lity
COPENHAGEN
UNIVERSITY
HOSPITAL
(Rigshospitalet)
Department of
Cardiothoracic
Surgery
GENTOFTE
UNIVERSITY
HOSPITAL
COPENHAGEN CENTRE FOR CANCER AND HEALTH
Municipality-based rehabilitation of cancer patients
BISPEBJERG
UNIVERSITY
HOSPITAL
DIAGNOSING ADJUVANT TREATMENT
HERLEV
UNIVERSITY
HOSPITAL
NORDSJÆLLANDS
HOSPITAL*
COPENHAGEN
UNIVERSITY
HOSPITAL
(Rigshospitalet)
Departments of
Oncology
Ho
spit
al
PATIENT PATHWAY
REHABILITATION
SURGERY
HOSPITAL-BASED FOLLOW-UP: HERLEV, NORDSJÆLLANDS*
GENTOFTE, BISPEBJERG AND COPENHAGEN UNIVERSITY HOSPITALS
* Nordsjællands Hospital did not participate in this project
24
Hypotheses
1. Preoperative home-based exercise is safe and feasible in patients with operable lung
cancer (Paper II)
2. Early postoperative rehabilitation with focus on exercise is safe and feasible in patients
with lung cancer, in a non-hospital setting (Paper II)
3. Improvement in physical capacity and HRQoL in patients following surgery for lung
cancer is achievable in a rehabilitation program in a non-hospital setting (Paper II-III)
4. A systematic literature search and review of the evidence will reveal that early initiation
of exercise, within two weeks following lung resection, will be more effective than
exercise initiated later (Paper IV)
Methods and Materials
Structure of the PROLUCA Project
The project Perioperative Rehabilitation in Operable LUng CAncer Patients (PROLUCA) was
developed in 2011. The randomized clinical trial (RCT) named PROLUCA RCT I aimed at
identifying the optimal timing of exercise to improve VO2peak in postoperative NSCLC patients.
This RCT consisted of a preoperative home-based intervention combined with a postoperative
rehabilitation program (Paper I). Due to an unexpected low recruitment rate, the study design in
PROLUCA RCT I was adjusted to the PROLUCA feasibility study, which focused on
recruitment to a pre and postoperative intervention, described in detail later in this section of the
thesis and in Papers II-III. In addition, a comprehensive literature search and a systematic review
were performed, as presented in Paper IV. Based on the results from the PROLUCA feasibility
study and the systematic review, a new RCT comparing early versus late postoperative exercise
interventions, was designed and conducted (PROLUCA II, not included in the present thesis).
Figure 3 presents the overall structure of this thesis.
25
Figure 3. Structure of the PROLUCA thesis
Methods (Paper II-III)
In order to reject or verify the four hypotheses, three different research designs were applied in
this PhD thesis. Paper I describes the setup in the PROLUCA RCT I, while Papers II-III examine
a single-centre four-arm prospective randomized controlled feasibility study in 40 patients with
operable lung cancer. Finally, Paper IV is a comprehensive systematic review and meta-analysis
of the available evidence from RCT comparable studies.
Recruitment and Eligibility
All patients were recruited from Department of Cardiothoracic Surgery, Copenhagen University
Hospital, Rigshospitalet. Potential subjects were identified and screened for eligibility and
informed by research coordinators at the involved hospitals (Bispebjerg University Hospital and
Gentofte University Hospital). After referral to curative lung cancer surgery, the subjects were
contacted by telephone and provided with a review of the study. If the subjects accepted to
participate, the baseline assessment was performed at Copenhagen Centre for Cancer and Health.
All patients had either histologically or cytologically confirmed NSCLC, stage I-IIIa (seventh
TNM classification system) (22), or strong substantiated suspicion of NSCLC, were at least 18
years of age, had World Health Organization (WHO) performance status 0–2 (76), were a
resident of the City of Copenhagen or a surrounding municipality, were able to read and
understand Danish, and were approved by the primary surgeon. The exclusion criteria were:
presence of metastatic disease or surgical inoperability, postoperative histologically verified
cancer disease different from lung cancer or no malignant disease at all, severe cardiac disease,
PROLUCA
RCT I
PROLUCA
FEASIBILITY
PERIOPERATIVE REHABILITATION POSTOPERATIVE
REHABILITATION
SYSTEMATIC
REVIEW
Paper I Paper II-III Paper IV
26
and contraindications to maximal exercise testing as described by the American Thoracic Society
(ATS) and by American College of Sports Medicine (ACSM) (77,78). From April 2012 to May
2013, forty patients age >18 years with NSCLC stages I to IIIa proven by biopsy and appointed
for curative lung cancer surgery at the Department of Cadiothoracic Surgery were included in the
feasibility study (Paper II-III).
Group Allocation (randomization)
In the feasibility study (Paper II-III), patients were individually randomized and allocated, after
completion of baseline assessments, to one of four intervention groups. The random allocation
sequences were executed externally by the Copenhagen Trial Unit, Centre for Clinical
Intervention Research and concealed from all the employees in the study. A permuted block
design with an allocation weight of 1:1:1:1 was used to create the group assignments.
Interventions
Figure 4 presents the timeline for the PROLUCA feasibility study. Group one did preoperative
home-based exercise combined with postoperative rehabilitation initiated two weeks after
surgery, while group two did preoperative home-based exercise combined with postoperative
rehabilitation initiated six weeks after surgery. Group three had postoperative rehabilitation
initiated two weeks after surgery and group four functioned as a control group with postoperative
rehabilitation initiated six weeks after surgery, which is a widespread practice in Denmark. The
intervention group assignment was not altered based on the participant’s adherence to the
randomly allocated study arm. The intention-to-treat analysis included all randomized
participants in their randomly assigned allocations, which included patients who were lost to
follow-up. To make sure that the groups were similar at baseline, patient randomization was
stratified based on type of surgery, i.e., VATS versus thoracotomy surgery.
27
Figure 4. Timeline for the PROLUCA feasibility study
Outcome Measures (Paper II-III)
The primary outcomes in the PROLUCA feasibility study (Paper II-III) were safety and
adherence to the intervention. Secondary outcomes were cardiorespiratory capacity, muscular
strength, walking distance, pulmonary capacity and patient-reported outcomes. All data were
collected according to the data assessment schedule presented in Table 1.
Table 1. Data assessment schedule in the PROLUCA feasibility study
2 weeks 6 weeks 14 weeks 18 weeks 26 weeks
1. Homeexercise
1. Early intervention
2. Late intervention
Enrollment
2 weeks
2. Home exercise
3. Early intervention
4.Late intervention
52 weeks
Group 1
Group 2
Group 3
Group 4
SURGERYDiagnosis
Last follow-up
28
Baselinea Follow-
upb Follow-
upc Follow-
upd Follow-
upe
Anthropometric data and cancer disease X X X X X
Physiological Measurements
Cardiorespiratory capacity (VO2peak) X X X X X
Six-minute walk distance (6MWD) X X X X X
1 repetition maximum (1RM) X X X X X
Heart rate (HR), Blood pressure (BP) X X X X X
Spirometric (FEV1/ FEV1%) X X X X X
Patient-Reported Outcome
Health-related quality of life (EORTC QLQ-C30) X X X X X
Health-related quality of life (FACT-L) X X X X X
Symptoms and side effects (EORTC–LC13) X X X X X
Anxiety and depression (HADS) X X X X X
Well-being (SF-36) X X X X X
Distress thermometer X X X X X
Lifestyle X X X X X
Sickness absence and work status X X X X X
Social support (MSPSS) X X X X X
Other Measurements
Serious adverse events / adverse events X X X X X
Adherence to exercise X X X
Postoperative complications (30 days) X
Duration of hospitalization X
Survival, histological diagnosis and TNM stage X
a Baseline (0 week) b Pre-operation (the day before surgery) c Post-intervention (14/18 weeks after surgery) d Six months after surgery e One year after surgery
Safety and Adherence
Safety in the present feasibility study was defined as number of serious adverse events or adverse
events and was registered by the staff in charge of the exercise sessions. Prior to every exercise
session, a cancer nurse specialist measured blood pressure (BP) and asked patients if they had
any symptoms consistent with side effects from the surgery, adjuvant treatment or the last
exercise session. Exercise that same day was cancelled if the patient experienced any of the
following symptoms/signs: fever (temperature >38◦ Celsius); diastolic BP <45 or >110
29
(measured); resting HR >110 (measured) or dizziness. For patients in chemotherapy, training
restrictions given to the patient from the hospital staff, based on levels of platelets <50×109/l,
leucocytes <1.0×109/l (79,80) or low levels of hemoglobin, were asked for. Postoperative
complications emerging within 30 days after surgery were registered based on medical records.
Adherence to exercise in the present thesis was defined as number of attended exercise sessions.
The attendance was registered by the patients at every exercise session in an exercise diary
logbook kept at the rehabilitation centre. If the patients did not show up for an exercise session,
they registered the reason for not attending. Adherence to the exercise intensity was monitored
by HR monitor and software (Polar Team,2 Polar Electro Oy, Professorintie 5, 90440 Kempele,
Finland) and an exercise diary logbook.
The following strategies were used to maximize adherence in all four intervention groups:
telephone-based follow-up, free parking in front of the centre, and remuneration for transport
expenses. A high degree of scheduling flexibility allowed patients to perform tests at a
convenient time so that they were prepared for competing demands, such as medical
appointments, work and family commitments.
Cardiorespiratory Capacity
The maximum oxygen uptake test is considered as a gold standard measurement of
cardiorespiratory capacity and can be expressed as VO2peak or VO2max (81,82). VO2peak is
commonly used in patient populations and VO2max is commonly used in healthy populations
(82). In the feasibility study, cardiorespiratory capacity (VO2peak) was evaluated by an
incremental test using an electromagnetically braked cycle ergometer (Lode Corival
Ergometer©) where inspired and expired gases were analyzed breath-by-breath by a metabolic
cart (JAEGER MasterScreen CPX©), patients began pedaling at seven watts and resistance
increased 10 watts every minute according to a predefined ramp protocol until exhaustion or a
symptom-limited VO2peak was achieved (e.g. pain, dizziness and anxiety). Calibration of the
equipment was performed prior to every test.
Muscular Strength
Muscular strength refers to the amount of force a muscle can produce with a single maximal
effort. In the feasibility study, muscle strength was measured by one repetition maximum (1RM),
defined as the greatest resistance that could be moved using the proper technique in a
TechnogymTM leg press and TechnogymTM chest press (83). Prior to testing, every patient did a
short warm-up, after which the resistance was increased so that the patients reached the
30
maximum in fewer than 10 attempts (to avoid fatigue). These procedures were standardized for
both leg and chest presses and the 1RM method is found reliable for measuring muscular
strength in upper and lower extremities in a healthy population (60-87 years) (84).
Walking Distance
Walking distance was measured by a test of 6MWD carried out over a pre-measured distance of
22 m and in accordance with the ATS statement (85). Participants were instructed to walk as far
as possible for six minutes, with feedback given on how much time remained after each minute.
6MWD is one of the most commonly used measures of functional capacity in lung care and has
demonstrated good reliability (test-retest reliability and consistency) and validity (criterion and
construct validity) in patients with lung cancer and in chronic obstructive lung disease (41,86–
90). Participants were monitored prior to and as close to termination of the test as possible with
portable pulse oximetry measuring arterial O2 saturation (Nellcor, OxiMax N-65©), which
provides the most accurate non-invasive assessment of blood arterial O2 saturation levels.
Pulmonary Capacity
In the feasibility study, pulmonary capacity was specified by assessing FEV1, the ratio of FEV1
compared with predicted values (FEV1%) and the FVC using a Triple V digital volume sensor©
connected to JAEGER MasterScreen CPX©. All pulmonary tests were carried out in accordance
with ATS guidelines, recording the best of three attempts carried out in a standing position and
performed with a nose clip, just as the patients were enthusiastically coached throughout the task
to perform their best using appropriate body language and phrases such as “keep going” (91).
Patient-Reported Outcome Measures
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire
Cancer 30 (EORTC QLQ-C30) / Lung Cancer 15 (EORTC QLQ-LC15)
The EORTC QLQ-C30 is a 30-item disease-specific multidimensional HRQoL questionnaire
designed for use in cancer patient populations. It is composed of both multi-item scales and
single-item measures that contain five independently functional subscales (physical, role,
cognitive, emotional and social); three symptom subscales (fatigue, pain and nausea and
vomiting); and a global health/QoL subscale. Furthermore, it also comprises six single items
assessing symptoms commonly reported by cancer patients (dyspnea, appetite loss, sleep
disturbance, constipation and diarrhea). All EORTC items are rated on a four-point Likert scale
ranging from 1 = “Not at all” to 4 = “Very much” and the raw EORTC scores are translated into
31
scores ranging from 0 to 100. A high score for a functional subscale or for the global health
status represents a high QoL, while a high score for a symptom scale represents a high level of
symptomatology. Lung cancer symptoms and treatment-related side effects were further assessed
using the EORTC QLQ–LC13, which is an additional page to the EORTC-QLQ specifically
designed to cover a wide range of lung cancer patients varying in disease stage and treatment
modality (92). The lung cancer-specific module, EORTC QLQ-LC13, comprises 13 questions
assessing lung cancer associated symptoms (cough, hemoptysis, dyspnea and site-specific pain);
treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy and alopecia); pain;
and medication. This questionnaire is designed for use in a wide range of lung cancer patients
varying in disease stage and treatment modality, including chemotherapy and/or radiotherapy
(93).
Functional Assessment of Cancer Therapy–Lung (FACT-L) questionnaire
HRQoL was also assessed using the FACT-L questionnaire, which is multidimensional and
specifically addresses patients with lung cancer. It is a combination of the 27-item FACT-G and
the nine-item lung cancer subscale (LCS). FACT-G contains four general subscales: physical
well-being; social/family well-being; emotional well-being; and functional well-being, while
LCS contains one lung cancer symptom-specific subscale that includes shortness of breath, loss
of weight and chest tightness. A total FACT-L score is obtained by summing the FACT-G score
with the LCS. This ranges from 0 to 136. All FACT-L items are rated on a five-point Likert scale
ranging from 0 = “Not at all” to 4 = “Very much”, with scores ranging from 0-24 (emotional
well-being), 0–28 (other four subscales), 0–84 (trial outcome index) and 0-136 (total score)
(25,94). Higher scores represent better QoL or fewer symptoms (95).
36-item Short Form Health Survey (SF-36)
General well-being was assessed using the 36-item SF-36 version 1, standard recall (four weeks)
questionnaire, which is a patient-reported survey of general health status consisting of eight
domains clustered to form two higher-order component scores, one on physical health and the
other on mental health. The former consists of four subscales: physical functioning; bodily pain;
general health perception; and physical role functioning, while the four subscales in the latter
comprise: emotional role functioning; social role functioning; mental health; and vitality. Items
are scored primarily on a five-point Likert scale, with subscale scores from 0-100 score and
component scores from 0-60. Higher the scores indicates better health (96,97).
32
Hospital Anxiety and Depression Scale (HADS)
Anxiety and depression were assessed using HADS, a 14-item questionnaire designed to
measure general anxiety and depression in patients with physical illness (98). One half of the 14
items addresses anxiety and the other depression, forming two scores ranging from 0-21 (98).
Scores are interpreted as: normal (0-7), mild (8-10), moderate (11-14) or severe (15-21)
symptoms of anxiety and depression (98).
The National Comprehensive Cancer Network (NCCN) Distress Thermometer
The NCCN® Distress Thermometer was used to assess physical distress in general, combined
with a ranking of physical problems, practical problems, family problems, emotional problems,
and spiritual/religious concerns. The NCCN® Distress Thermometer is not yet tested for validity
in patients with NSCLC; however, it is found to be valid in a population diagnosed with breast
cancer. This questionnaire consists of a single item, with responses ranging from 0 to 10 (99).
Multidimensional Scale of Perceived Social Support (MSPSS)
The 12-item MSPSS was used to assess social support, with items scored on a seven-point Likert
scale ranging from 1 = “Very strongly disagree” to 7 = “Very strongly agree”. The scale yields
three subscale scores for: family, friends and significant others, and a total perceived social
support score that has a summary score (100,101). In addition to the MSPSS questionnaire,
responses to seven questions on the relationship with other cancer patients were collected that
addressed support, network, social interactions and sharing hope for the future.
Preoperative Exercise Training Protocol (Paper II-III)
The preoperative exercise program contained a home-based exercise program that was
individually designed according to functional status and comorbidity for each patient randomized
to the preoperative intervention based on the physical activity guidelines for cancer patients
recommend by the DHA and the ACSM (36,73). The program aimed at cardiovascular exercise
of a moderate to vigorous intensity (~60-80% of maximal heart rate (HRmax)) for at least 30
minutes every day until surgery. To assure the exercise intensity, the patients were instructed to
do exercises that made it impossible to talk because of breathlessness. Jointly with the patient, a
suitable modality of exercise was chosen to be the program’s main activity, e.g.,
walking/running, stair climbing or bicycling. The exercise period varied in length based on the
time available before surgery. The preoperative exercise was monitored by HR monitor and
33
software (Polar Team2, Polar Electro Oy, Professorintie 5, 90440 Kempele, Finland) and an
exercise diary logbook.
Postoperative Exercise Training Protocol (Paper II-III)
Trained physiotherapists and cancer nurse specialists supervised the postoperative exercise
program following principles recommended by ACSM (36,102). The ACSM guidelines were
developed based on existing recommendations for exercise from ACSM, the American Heart
Association (103) the American Cancer Society (104), and the physical activity guidelines for
the American population described by the United States Department of Health and Human
Services (105). It is recommended that exercise prescriptions are individualized according to
treatment of the cancer patient and their general health condition (36). As a result, the
postoperative exercise programs were individually tailored and consisted of supervised
resistance exercise and group-based cardiorespiratory exercise twice a week (60 minutes/session)
on non-consecutive days for 12 weeks, for a total of 24 sessions. The postoperative exercise
included the following: warm-up (five minutes) and cardiorespiratory exercise (25 minutes) on
an ergometer bike (BODY BIKE Classic Supreme©) and individually tailored resistance
exercise (25 minutes) carried out using five machines (TechnogymTM): the leg press, chest press,
leg extension, pull to chest and pull down (upper body).
The cardiorespiratory exercise consisted of high intensity interval exercise, including a warm-up
period in which the participants aimed at reaching a level at 85% of their individually determined
HRmax (5 minutes) followed by a short rest (1 minute). The duration of the high intensity
interval exercises was 25 minutes. At each interval (1-2 minutes), the participants aimed at
reaching a level of 85-100% of their individually determined HRmax in each interval, followed
by a short rest (1 minute). The high intensity interval exercise was followed by a cool down
period (2 minutes). After the cardiorespiratory exercise, supervised breathing exercises,
stretching and tension-release techniques were performed for approximately five minutes (106).
The first four weeks, of the intervention, the cardiorespiratory intensity of ~50-60% of individual
determined HRmax and in the next eight weeks, the intensity increased to a moderate to high
intensity at ~70-90%. The exercise protocol prescribed resistance exercise comprising three sets
per exercise at an intensity of ~60-80% of 1RM two times a week for 12 weeks. Every other
week, the resistance was progressively increased and the number of repetitions reduced, starting
out at 12 repetitions in three sets, progressing to 10 repetitions in three sets, to a final eight
34
repetitions in three sets. The postoperative exercise intervention was combined with access to the
other rehabilitation services available at the municipal rehabilitation centre in Copenhagen. Prior
to the first postoperative exercise session, every patient was asked about rehabilitation needs
according to a professional rehabilitation guide covering the following topics: disease specific,
social, network, relatives, psychological, existential, diet, smoking, alcohol, physical activity,
sexuality, sleep and stress. The theoretical framework by WHO on International Classification of
Functioning (2001) (107), Bandura et al’s (1977) (108) self-efficacy theory and Miller et al’s
(1996) (109) motivational interviewing formed the basis of this rehabilitation guide. The
postoperative exercise intervention comprised 24 group-based exercise sessions, three individual
counseling sessions and three group-based lessons in health-promoting behavior. If the patients
had special needs in terms of smoking cessation, nutritional counseling or patient education, this
was also offered as part of the rehabilitation. Figure 1 presents the rehabilitation services
available at the municipal rehabilitation centre in Copenhagen.
Methods and Materials in the Systematic Review (Paper IV)
Carried out in accordance with the Cochrane Handbook for Systematic Reviews of Interventions
(2011) and reported in accordance with the PRISMA statement guidelines, Paper IV is a
systematic review registered in the PROSPERO database under the registration number
CRD42016027412 (110,111).
Search Strategy
A literature search matrix was used for MEDLINE and was adapted for use in the other
databases: Embase, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL and
PEDro (Table 2). The search strategy focused on two overall clusters: NSCLC and rehabilitation,
with their associated synonyms and combined with AND, as shown in Table 2. No limitations
were used in the electronic searches to avoid unintended exclusion of relevant trials. In order to
identify additional trials, all reference lists of all primary studies and review articles were
screened. Experts in the field of exercise and NSCLC were contacted in order to identify
unpublished research. A search was also done of clinicaltrials.gov to identify ongoing, as yet
unpublished trials.
35
Table 2. Matrix of the search strategy for MEDLINE via PubMed
‘NSCLC’ AND ‘Rehabilitation’
Carcinoma, Non-Small-Cell Lung[Mesh] Motor Activity[Mesh]
OR OR nsclc[ti/ab] physical activit*[ti/ab]
OR OR
non small cell*[ti/ab]
OR nonsmall
cell*[ti/ab]
AND
lung cancer*[ti/ab] OR
lung neoplasm*[ti/ab]
OR lung
carcinoma*[ti/ab] OR
lung tumor*[ti/ab] OR
lung tumour*[ti/ab]
motor activit*[ti/ab]
OR
locomotor activit*[ti/ab]
OR
exercis*[ti/ab]
OR
training[ti/ab]
OR
physical conditioning[ti/ab]
OR
Rehabilitation[Mesh]
OR
rehabilitation[ti/ab]
OR
OR Sports[Mesh] Pneumonectomy[Mesh] OR
OR sport*[ti/ab] Pneumonectom*[ti/ab] OR
OR fitness[ti/ab] Lobectom*[ti/ab] OR
OR endurance[ti/ab] lung resection*[ti/ab] OR
aerobic*[ti/ab] OR
Exercise Movement Techniques[Mesh]
Inclusion Criteria and Data Extraction
Eligibility criteria were RCTs that assessed the effects of postoperative exercise interventions in
patients undergoing resection for NSCLC, where patients were allocated to receive exercise
compared to a control group. Studies and abstracts published in the following languages were
eligible for inclusion: English, one of the Scandinavian languages and German. The study
population was patients receiving any type of lung resection performed with VATS or
thoracotomy procedures. At least 50% of the population had to have gone through an operation
for NSCLC in order to avoid a comparison of effect measures in different populations. The
interventions in the included trials comprised any type of exercise involving bodily movements
produced by skeletal muscles (aerobic exercise, resistance exercise, ambulation and mobility
36
exercise) initiated within one year after lung resection. Supervised and/or unsupervised exercise
performed individually or in groups was also eligible intervention criteria. The type, intensity,
frequency and duration of the exercise interventions were not a constraint but were recorded
where possible. Control groups were considered eligible if they contained non-intervention
control, usual care, waiting-list control or add-on treatments. Primary outcomes in the studies
should be cardiorespiratory capacity measured by an maximum exercise capacity test
(e.g.VO2peak or VO2max) or 6MWD measured as a primary or secondary outcome. Secondary
outcomes in the studies were HRQoL measured by one of the following questionnaires: Generic
SF-36 (97), cancer-specific EORTC QLQ-C30 (93) and the disease-specific patient-reported
outcome FACT-L (95). All references identified were imported into the web-based software
platform covidence.org. Selection of trials, risk of bias assessment and extraction of data were
managed in this software. Two review authors (first and second author Paper IV) independently
screened titles and abstracts, after which full-text screening was undertaken using the search
strategy to determine eligibility for inclusion. Their decisions were recorded and disagreements
were resolved by consensus. Two review authors (first and second author Paper IV)
independently extracted data using a predefined form based on the Cochrane Collaboration’s
checklist of items to consider in data extraction. Data comprised details of the trials, participant
characteristics and results at postoperative time points. Disagreements on extraction of data were
resolved by discussion. In cases of missing data, the authors of the trials were contacted and
asked if they could provide the missing details. The review process continued without the
information if the trial authors could not provide the requested information within one month.
Results from intention-to-treat analyses were prioritized in the analysis of the present review
and, if possible, results on missing individuals were recorded as well.
Risk of Bias and Quality of Evidence Assessment
Two review authors (first and second author Paper IV) independently assessed the risk of bias
for all of the included trials, evaluated as either high, low or unclear risk of bias, using the
Cochrane Collaboration’s tool for assessing risk of bias (111). Quality of evidence was assessed
using Grading of Recommendations, Assessment, Development and Evaluation (GRADE)
(2004) (112). The body of evidence identified for each outcome was rated as high, moderate, low
or very low quality based on the following five factors: risk of bias, indirectness, inconsistency,
imprecision and publication bias. Disagreements were resolved by discussion, or when
37
necessary, by a third reviewer (third author Paper IV), who was consulted and then agreement
reached.
Statistical Considerations
Data Analysis in the Feasibility Study (Paper II-III)
Descriptive statistics were used to assess the safety and adherence. Baseline values of the study
populations were compared to values measured at post-intervention, which is 14 weeks post
surgery in the early intervention groups and 18 weeks post surgery in the late intervention
groups, and one-year follow-up. The values are expressed as mean + standard deviations (SD).
Paired t-tests were used to compare the physical outcomes between the early postoperative
exercise intervention and the late postoperative exercise intervention. In the analysis, groups one
and three were merged into one group (early postoperative exercise) and group two and four
were merged into one group (late exercise intervention group). Paired t-tests were also
performed to reveal trends in patients who exercised for more or less than 70% of the exercise
sessions. A cut-off at 70% for adherence to exercise was used as a validity criteria for the
included RCT in the ACSM guidelines for cancer patients (36). The overall effect of time on the
patient-reported outcomes was evaluated using repeated measures analysis of variance
(ANOVA) and was calculated using the mixed linear models. Estimated scale mean scores were
reported as the mean with corresponding 95% CIs and compared to aged-matched reference data
when available. The reference data was a random sample of 3,080 individuals, drawn from the
Danish Civil Registration System for EORTC QLQ-C30 (113), while for SF-36 (114) it was a
random sample of 6000 individuals, also drawn the Danish Civil Registration System. To
analyze the changes in smoking, alcohol and physical activity habits, logistic, Poisson and
multinomial logistic regression models were used, respectively. The clustered nature of the data
was taken into account using generalized estimating equation (115,116), implemented in the
generalized linear model (GENMOD). Wald tests were used to evaluate changes over time.
Statistical significance was set at p<0.05 and all statistical analyses were conducted using SAS
software, version 9.4 of the SAS System (Copyright © 2014, SAS Institute Inc., Cary, NC,
U.S.A.).
38
Statistical Analyses in the Systematic Review (Paper IV)
For continuous outcomes, standardized mean differences (SMD) and the corresponding 95% CI
were used for analysis as the included studies assessed the outcomes of interest in a variety of
ways. To calculate the SMDs, the mean change scores and the corresponding SDs were extracted
from the trials when these were reported. If mean change scores and/or SDs of the mean change
scores were not reported, these were calculated based on the baseline and follow-up means and
SDs, but only in cases where they were not provided, as recommended in the Cochrane
Handbook (2011) (111). The calculated SDs of the mean change scores from baseline were
estimated by imputing a correlation coefficient in the formula below to allow the use of paired
data (117,118):
𝑆𝐷𝑐ℎ𝑎𝑛𝑔𝑒 = √𝑆𝐷𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒2 + 𝑆𝐷𝑓𝑜𝑙𝑙𝑜𝑤−𝑢𝑝
2 − (2 𝑥 𝑐𝑜𝑟𝑟 𝑥 𝑆𝐷𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑥 𝑆𝐷𝑓𝑜𝑙𝑙𝑜𝑤−𝑢𝑝).
When calculating the SDs of mean change scores, a correlation coefficients (r) is needed. As the
correlation coefficients were not reported in the studies, correlation coefficients from similar
populations were used concerning the following outcomes: VO2peak r=0.927 (119), 6MWD
r=0.93 (89), SF-36 physical and mental component scores r=0.94 (120) and the EORTC QLQ-
C30 physical functioning score r=0.85 (121). In cases with a discrepancy between the reported
mean change scores and the reported data for baseline, the calculated mean change scores were
used for analysis. If more than two time points were reported in the included studies, the follow-
up closest to 12 weeks after initiation of the intervention, was selected as “short-term”. Long
follow-up beyond six months was selected as “long-term”. The effect was interpreted based on
the magnitude of SMD, using the Cohen’s guidelines: no effect under 0.2; small effect SMD =
0.2; medium SMD = 0.5; and large SMD = 0.8 (122).
All statistical analyses and forest plots were conducted in StataCorp 2013, Stata Statistical
Software: Release 13 (StataCorp LP, College Station, TX, U.S.A.). Risk of bias summary and
graphs were conducted in Review Manager (RevMan), version 5.3, Copenhagen, Denmark: The
Nordic Cochrane Centre, The Cochrane Collaboration, 2014. A summary of the findings in
Paper IV was generated in GRADEpro GDT (GRADEpro Guideline Development Tool,
McMaster University, 2015 (developed by Evidence Prime).
To calculate the overall treatment effect, a random-effects model was chosen using DerSimonian
and Laird’s method (123). Clinical heterogeneity was considered by assessing differences among
the trials concerning patient populations (e.g., age, degree of surgery and comorbidities) and
exercise interventions (e.g., type, intensity, frequency, duration). The percentage of the
39
variability in effect estimates due to heterogeneity was evaluated using the I-squared test (I2),
which is suitable in the present review because it is independent of the number of trials. A higher
percentage indicates statistical heterogeneity, and approximately 25% or less is considered to be
low, around 50% is considered as moderate and 75% or above is high. Heterogeneity above 50%
is interpreted as a considerable level of heterogeneity (124).
Sensitivity Analysis
To assess the effect of trials initiating exercise interventions early (within the first two weeks
after surgery for lung cancer) compared to the effect of trials initiating exercise interventions
later than two weeks after surgery, a sensitivity analysis was carried out between trials initiating
exercise interventions before two weeks after surgery and trials initiating exercise later than two
weeks. This sensitivity analysis was conducted on short-term follow-up. A cut-off at two weeks
after surgery was a pragmatic approach based on clinical reflections concerning tissue healing
and when exercising would be safe. The sensitivity analysis aimed at identifying the optimal
time of onset of postoperative rehabilitation to patients with NSCLC.
Ethical Considerations
The feasibility study (Paper II-III) was reported according to the CONsolidated Standards of
Reporting Trials (CONSORT) statement for non-pharmacologic interventions and the World
Medical Association Declaration of Helsinki Declaration (125,126). All participants gave
informed written consent prior to participation in any study procedures. The Danish National
Committee on Health Research Ethics (H-3-2012-028) and the Danish Data Protection Agency
approved the handling of data (2007-58-0015) in the feasibility study.
Results from the Feasibility Study (Paper II-III)
Patient Characteristics and Recruitment
The final number of patients screened for eligibility and referred for surgery was 180, of whom
124 were eligible. A total of 40 patients (32%) were included in the feasibility study and
randomized as presented in the flow chart in Figure 5. Table 3 presents the characteristics of the
40 patients. The patients had a mean age of 68 years (table 3), the majority of them were retired
(70%), 15% were currently employed, 5% unemployed, 5% enrolled in education, 2.5% off work
40
sick and 2.5% did not answer the question on working status. The most frequent comorbidities
were hypertension, dyslipidemia, rheumatic disease and COPD. Sixteen patients had more than
two comorbidities and five patients had no comorbidities. Twenty-five percent currently smoked,
70% were ex-smokers and 5% had never smoked. Twenty-eight percent stated that their level of
alcohol consumption was above the DHA’s recommended level, which is more than seven units
per week for females and over 14 units per week for males. The majority of patients (78%) had
gone through VATS and nine patients (22%) had undergone a thoracotomy. Thirty-three percent
(13 patients) were treated with adjuvant chemotherapy. The extent of resection was as follows:
lobectomy (83%), pneumonectomy (2%), bilobectomy (5%), wedge resection (8%) and VATS
segmental resection (2%). Patients who did not attend the study primarily reported that the
reason was either due to logistical problems or concerns about their upcoming surgery (Figure
5).
41
Figure 5. Flow PROLUCA feasibility study
Table 3. Baseline characteristics
Variables Total n=40 Early exercise n=18
Group 1+ 3
Late exercise n=22
Group 2+ 4
Age, years, median
(range)
68 (36-85) 67 (36-79) 71 (56-86)
42
Female, n (%) 24 (60%) 10 (56%) 14 (64%)
Body mass index,
kg/m2, mean (SD)
25 (5) 25 (5) 25 (4)
Academic
professional degree
<3 years, n (%)
17 (43%) 6 (33%) 11 (50%)
Smoking history, n=40 (groups 1 and 3, n=18; groups 2 and 4, n=22)
Currently smoking,
n (%)
10 (25%) 7 (39%) 3 (14%)
Never smoked, n (%) 2 (5%) 1 (6%) 1 (5%)
Ex-smoker, n (%) 28 (70%) 10 (55%) 18 (81%)
Years smoking, mean
(SD)
41 (15) 44 (12) 38 (13)
Presence of comorbidity
(five patients had none of the comorbidities below)
Hypertension, n (%) 15 (38%) 6 (33%) 9 (41%)
Dyslipidemia, n (%) 9 (23%) 4 (22%) 5 (23%)
Diabetes, n (%) 6 (15%) 3 (17%) 3 (14%)
Atrial fibrillation,
n (%)
2 (5%) 0 2 (9%)
COPD, n (%) 8 (20%) 2 (11%) 6 (27%)
Rheumatic diseases,
n (%)
12 (30%) 5 (28%) 7 (32%)
Previous other type
of cancer, n (%)
6 (15%) 4 (22%) 2 (9%)
Depression, n (%) 4 (10%) 1 (6%) 3 (14%)
Medication, number
of drugs, median
(range)
3 (1-6) 2 (1-5) 3 (2-6)
Pulmonary function
FEV1, L/s, mean (SD) 2.4 (0.6) 2.5 (0.5) 2.3 (0.6)
FEV1, L/s, % predicted
(SD)
94 (23.7) 95 (26.1) 93 (22.2)
FEV1 /VC, %, mean
(SD)
67.4 (8.7) 68 (6) 68(10)
Cardiorespiratory capacity
43
Fitness, mL/kg/min,
mean (SD)
19.4 (5) 21.5 (6) 17.6 (4)
Peak oxygen uptake,
L/min, mean (SD)
1.40 (0.39) 1.53 (0.33) 1.28 (0.40)
6MWD
Meter (SD)
477 (81) 497 (92) 461 (70)
TNM stage
Stage I (a+b), n (%) 11(27%) 5 (28%) 6 (27%)
Stage II (a+b), n (%) 24 (60%) 12 (67%) 12 (55%)
Stage IIIa, n (%) 5 (13%) 1(5%) 4 (18%)
Safety
No adverse events were reported or observed during the home-based preoperative exercise
program or the postoperative exercise program, and no patients had spontaneous or unexpected
reactions to exercising two weeks after surgery.
Postoperative Complications, Recurrence, and Mortality
Only one postoperative complication (pulmonary pneumatocele) occurred during the early
exercise intervention and it was not evaluated as an adverse event caused by the exercise. All
other postoperative complications were of a pulmonary and cardiac nature that occurred before
the patients had initiated the exercise intervention. Within 30 days after surgery, the prevalence
of pulmonary postoperative complications was 23% and was found to be highest in the group
who initiated exercise two weeks after surgery (groups 1 and 3) (Table 4). Cardiac complications
occurred in 13% of all complications and the distribution was even between the groups with
early and late exercise. Recurrence was experienced in two patients and three patients died
within the first year after surgery (Table 4).
44
Table 4. Postoperative complications, recurrence and mortality
Pulmonary complications, n=40 (%)* 9 (23%)
Early, n=18 (%) 6 (33%)
Late, n=22 (%) 3 (14%)
Cardiac complications, n=40 (%)* 5 (13%)
Early, n=18 (%) 2 (11%)
Late, n=22 (%) 3 (14%)
Recurrence, n=40 (%) 2 (5%)
Mortality, n=40 (%) 3 (8%)
*Data collected 30 days after surgery
Data collected at one-year follow-up
Dropouts
Eleven patients dropped out (27%) during the intervention, primarily due to either a lack of
motivation to complete or side effects from the adjuvant chemotherapy. Patients who were
treated with adjuvant chemotherapy were evenly distributed between the group of completers
and the group of dropouts (Paper II). In the group of patients who exercised for 70-100% of the
24 exercise sessions, the prevalence of patients treated with adjuvant chemotherapy was lower
compared to the group of patients who exercised 0-69% (Paper II). No difference was found
concerning demographic data, stage of disease or type of surgery between the group of
completers and the group of dropouts. The prevalence of dropouts was evenly distributed
between the groups with early-initiated exercise and the group with late-initiated exercise (Table
5).
Adherence to Home-based Preoperative Exercise
Six out of 18 (30%) patients randomized to preoperative exercise were not able to receive
instruction in preoperative home-based exercise. The contributory cause was a combination of
medical procedures and lack of time prior to surgery, while one patient received instructions but
did not start the program due to a lack of motivation. Eighteen were randomized to the home-
based exercise program and the average number of days possible for exercise before surgery was
eight, with a range between 2-15 days. Only three out of 12 patients managed to exercise daily
prior to surgery (Table 5).
45
Adherence to Supervised Postoperative Group Exercise
The supervised group exercise program was completed by 73% of the patients. Adherence to the
24 group-based exercise sessions post surgery was >70% in 15 patients out of 29 (Table 5). Four
patients out of the 29 did not start exercising; since the study is an intention-to-treat study, results
from all 29 are provided. Additionally, analysis of the 25 patients who completed the exercise
program post surgery was also carried out but the results did not change the significance of the
results presented in Table 5. Consequently, the results for the completers alone are not included
in the present thesis. Patients cancelled exercise sessions primarily because they were
hospitalized/had appointments at the hospital, lacked motivation or did not have the time to
exercise. Adherence was equal in the group with early-initiated exercise (groups 1 and 3) and in
the group with late exercise (groups 2 and 4) (Table 5).
The average onset of exercise was 18 days post surgery in the early intervention group (groups 1
and 3), with a range of 13 to 29 days. In the late intervention group, the average onset of exercise
was 47 days, with a range of 22 to 80. In the early intervention group, only one patient started
exercise 49 days after surgery, which was close to the time of initiation of exercise in the late
intervention (groups 2 and 4). As a result, this patient was no longer categorized as a patient in
the early intervention group. Patients who performed preoperative exercise were evenly
distributed between the clusters that exercised for at least 70%, or for less than 70%, of the
postoperative sessions. During the 24 exercise sessions, the strength exercise was performed
with the intensity at 67% (SD 20) of 1RM for the chest press and 69% (SD 22) of 1RM for the
leg press. In the first four weeks of the 24 sessions, the intensity of the cardiorespiratory exercise
was at 74% (SD 8) of the individually determined HRmax and in the last eight weeks, it was at
77% (SD 4) of the individually determined HRmax.
46
Table 5. Adherence to perioperative exercise
Preoperative exercise (home-based) (n=18)
Instruction given to, n (%) 12 (67%)
Possible days for exercise, mean (range) 8 (2-15)
Days of self-reported exercise out of days possible (%) (n=12)
Exercise >70%, n (%) 8 (67%)
Exercise <70%, n (%) 4 (33%)
Postoperative exercise adherence to 24 sessions (group exercise) (n=29)
Exercise >70%, n (%) 15 (52%)
Exercise <70%, n (%) 14 (48%)
Participation > 70% in early and late postoperative intervention (n=15)
Early exercise, n (%) 7 (47%)
Late exercise, n (%) 8 (53%)
Drop-outs in early and late postoperative intervention (n=11)
Early exercise, n (%) 5 (45%)
Late exercise, n (%) 6 (55%)
Initiation of exercise: Early (n=15) and late (n=16) intervention groups
Early, number of days after surgery, mean (range) 18 (13-29)
Late, number of days after surgery, mean (range) 47 (22-80)
Changes in Physiological Capacity
Changes in physiological capacity were evaluated in relation to adherence to exercise. Walking
distance increased significantly post-intervention for patients who participated in at least 70% of
the sessions, with a mean difference between baseline and post-intervention of 28 meters (95%
CI: 4 to 51, p=0.0229). At one-year follow-up no significant effect on walking distance was
found. Results for the leg and chest press showed a significant improvement in strength for
patients who participated in at least 70% of the sessions. This improvement was found to be 30
kilos for the leg press (95% CI: 5 to 55, p=0.0220) and five kilos for the chest press (95% CI: 2
to 8, P=0.0029) at post-intervention. The mean difference between baseline and one-year follow-
up on the leg press was an improvement of 18 kilos (95% CI: 1 to 36, p=0.0443) and for the
chest press the improvement was four kilos (95% CI: 1 to 7, p= 0.0129). Fitness decreased,
independent of adherence to exercise, from baseline to post-intervention by 1.9 mL/kg/min (95%
47
CI: -3.9 to 0.2, p=0.0741) and the decrease was retained at 1.8 mL/kg/min (95% CI: -3.7 to 0.11,
p=0.0637) at the one-year follow-up.
Changes in HRQoL
The FACT-L total score and LCS subscale showed a statistically significant improvement across
the five time points (Figure 6a, p=0.0163; and 6b, p=0.0421). The EORTC-QLQ-C30 functional
scales showed increasing levels of global QoL (Figure 7a, p=0.0032). Results from SF-36
showed improvements for the mental health component score (Figure 7b, p=0.0004). The SF-36
domain bodily pain showed no overall statistically significant difference between the five time
points (p=0.1069), but post hoc comparisons indicated that scores six months and one year after
surgery were higher than the baseline scores (7.3 and 7.6 points, respectively). For further results
on patient-reported outcomes, see Paper III.
Figure 6a and 6b. FACT-L total score, score range 0-136 (6a), high scores indicate good HRQoL, and FACT-L LCS (6b),
score range 0-28, high scores indicate low level of symptoms reported
Baseline Pre surgery Post intervention Six months One-year
Time
0
7
14
21
28
Mea
n sc
ore
(9
5%
CI)
P-value 0.0421
FACT-L Lung cancer subscale
Baseline Pre surgery Post intervention Six months One-year
Time
0
7
14
21
28
Mea
n sc
ore
(9
5%
CI)
P-value 0.0421
FACT-L Lung cancer subscale
Baseline Six months
Time
0
10
20
30
40
50
60
70
80
90
100
Mea
n sc
ore
(9
5%
CI)
Reference population mean
P-value 0.0032
EORTC-QLQ Global quality of life
Baseline Six months
Time
0
10
20
30
40
50
60
70
80
90
100
Mea
n sc
ore
(9
5%
CI)
Reference population mean
P-value 0.0032
EORTC-QLQ Global quality of life
6a 6b
7a 7b
48
Figure 7a. EORTC-QLQ Global QoL, score range 0-100, high scores indicate good HRQoL. Figure 7b. SF-36 Mental
component score (6b), score range 0-60, high scores indicate good HRQoL in both questionnaires, CI
Changes in Smoking, Alcohol, and Physical Activity Habits
Changes in smoking, alcohol and physical activity habits showed a reduction in the number of
patients currently smoking, from 25% at baseline to 5% after the intervention, followed by an
increase to 12% one year after surgery. These percentages did not differ significantly (Wald test
X2=8.47, degrees of freedom (df)=4, P=0.0759, P for trend 0.0579). A similar pattern was seen
in connection with alcohol consumption. At baseline, 28% consumed more alcohol than DHA
recommends. This amount dropped to 7% post-intervention, followed by an increase to 14% one
year after surgery. Comparing the number of drinks per week using Poisson regression did not
indicate significant differences across the five time points (Wald test X2=4.33, df=4, P=0.3634, P
for trend 0.1371). Physical inactivity dropped from 15% at baseline to 4% one year after surgery.
Comparing the distribution of the ordinal variable in multinomial logit regression models
adjusted for the level three months before diagnosis did not indicate significant differences
across the five time points (Wald test X2=8.10, df=4, P=0.0881, P for trend 0.6985).
Results from the Systematic Review (Paper IV)
Electronic databases were searched on the February 17, 2016 and resulted in 6191 hits: 1641
from MEDLINE, 3291 from Embase, 270 from the Cochrane Central Register of Controlled
Trials (CENTRAL), 970 from CINAHL and 19 from PEDro. The number of duplicates was
1661, resulting in 4530 unique papers. Based on title and abstract, 4464 papers were excluded,
resulting in 66 papers read in full text. Out of the 66, 62 studies were excluded as they did not
meet the inclusion criteria. The present review included four RCTs involving 262 participants
(65,127–129). Three of the studies randomized the participants into one of two groups: an
exercise intervention or a control group (65,127,128). The fourth study randomized the
participants into one of three groups: exercise intervention 1, exercise intervention 2 or a control
group (129).This study was divided into two studies in the analysis, where each intervention
group was compared to half of the control group (111).
Twelve were in a language other than those listed in our criteria and three had missing data,
which meant they were excluded. The first of the last-mentioned studies was contacted but the
authors were unable to provide postoperative measurements of exercise capacity (130); the
49
second study was a conference article that was insufficient due to low completion of the
intervention and a large amount of missing data (131); and the third one was unable to provide
the missing data on exercise capacity and HRQoL (132). Figure 8 presents a flowchart of the
search process based on the PRISMA template (133). For more details about excluded
references, see Paper IV.
Figure 8. Study flow diagram
The studies which originated from the UK, Denmark, Belgium and Norway and were published
from 2011–2015. Two of them conducted the interventions in a hospital setting after discharge
(128,129), with participants in one study exercising during admission with subsequent home
50
training (127). In the fourth study, the intervention was conducted in local fitness centers after
discharge (65). All four studies included mainly participants who had undergone lung resection
for NSCLC. Both sexes were included and the mean age was above 60 years in all study groups.
The majority of the participants went through open surgery (range 77–96%) and the lung cancer
stages were equally distributed between control and exercise groups, except in one study, where
four participants with stage IV NSCLC were randomized to the control group and none to the
exercise group. For a summary of included studies, see further details in Paper IV.
Exercise interventions included a component with aerobic exercise and resistance training,
except for intervention two in the three-armed RCT, which included exercise and whole body
vibration (129). The intervention components varied in intensity, frequency and duration across
the studies. The intensity of the aerobic exercises, which consisted of either walking or biking,
varied from 60-95% of HRmax. The frequency of training varied from one session per week for
10 weeks (128) to three times a week for 12 (129) or 20 (65) weeks. The exercise interventions
were initiated after five days (127), three weeks (128), 4-6 weeks (65) or within eight weeks
(129) following lung resection.
Baseline measurements in Arbane et al’s (2011) (127) study were conducted pre-surgery as the
study initiated exercise pre-surgery and until day five post surgery. In order to rule out variance
due to operation outcomes, we decided in the present study to use the first measurement on day
five post surgery as the “baseline” in the present review.
Additionally, Arbane et al’s (2011) results showed no statistical or clinical effect of early
exercise captured by the day-five post surgery measurement, even though the intervention group
had a mean distance that was 28 meters further than the control group (measured at day five
postoperatively) (127). The minimal important difference (MID) in the 6MWD in patients with
lung cancer is 42 meters (87).
The control groups received usual care consisting of a monthly telephone call from the research
team, which provided education (127), one hour of individual instruction in home exercises
(128), no advice beyond general information from the hospitals (65) and even discouraged
improving their exercise tolerance with professional help (129).
Exercise capacity was reported in all four studies, two of which reported VO2peak (65,129) and
three of which reported 6MWD (127–129). HRQoL was reported in three studies, two of which
reported SF-36 in physical and mental component scores (65,128), and one study reported the
EORTC QLQ-C30 physical functioning score (129). One study only had one measurement of
HRQoL post surgery, which is why that outcome was not extracted (127). All of the studies had
51
collected a short-term follow-up at completion of their interventions, and one study had collected
an additional long-term follow-up one year after baseline (128).
Risk of Bias
Figure 9 presents the overall assessment of risk of bias across the studies, while Paper IV
presents the risk of bias for the individual studies.
All the studies reviewed were at high risk of performance bias because blinding of participants is
difficult in exercise interventions. The majority of studies were at high or unclear risk of
detection bias and reporting bias as the outcome assessors were not blinded and the relevant
predefined outcomes were not evaluated due to lack of completion of outcome measures or no
trial registry. The section called “Summary of included studies” in Paper IV contains a detailed
description of the assessment of risk of bias.
Figure 9. Risk of bias graph: review of authors’ assessment of each risk of bias item presented as percentages
across all included studies
Effect of Intervention
All meta-analyses were conducted using a random-effects model after assessment of clinical
heterogeneity between studies, particular in the exercise interventions. VO2peak is considered
the gold standard measurement of cardiorespiratory capacity, therefore when both VO2peak and
6MWD were available, VO2peak was chosen. Results, measured post-intervention, stated as
short-term, showed a significantly higher exercise capacity in the intervention group compared to
the control group (SMD 0.48; 95% CI 0.04 to 0.93), reflecting a small to moderate effect size
(Figure 10.). The I2 was 61.6%, suggesting moderate variations between intervention effects. The
52
study with a long-term follow-up showed no effect on exercise capacity after one year from
baseline (SMD 0.09; 95% CI -0.44 to 0.61). The results are not illustrated.
Figure 10. Forest plot: effect of exercise capacity in exercise group versus control group (short-term)
The SF-36 physical component score was pooled in a meta-analysis with the EORTC QLQ-C30
physical functioning score. The physical component of HRQoL was significantly higher in the
intervention group compared to the control group (SMD 0.50; 95% CI 0.19 to 0.82) when
dealing with short-term effect, reflecting a moderate effect size (Figure 11). I2 was 0%,
suggesting a small variation between intervention effects.
According to the one study with long-term follow-up, there was no effect on the physical
component of HRQoL in the long-term (SMD -0.27; 95% CI -0.78 to 0.25). The SF-36 mental
component score was reported in two studies and pooled in a meta-analysis. There was no effect
on the mental component of HRQoL (SMD 0.53; 95% CI -0.78 to 1.83) concerning short-term
effect, nor at long-term follow-up (SMD -0.48; 95% CI -1.01 to 0.04). The results are not
illustrated.
Only one study initiated exercise intervention early, within two weeks after surgery (127). This
study showed no effect on exercise capacity in the short-term (SMD 0.09; 95% CI -0.57 to 0.74).
In three studies that initiated exercise interventions later (65,128,129), >2 weeks after surgery, in
contrast, the exercise capacity was significantly higher in the intervention group compared to the
53
control group in the short-term (SMD 0.58; 95% CI 0.07 to 1.09), reflecting a moderate effect
size. There was no difference between the effect of late and early-initiated exercise intervention.
I2 for exercise interventions initiated late was 65.6%, suggesting moderate variation between
intervention effects.
Figure 11. Forest plot: effect of the physical component of HRQoL in exercise group versus control group (short-
term)
An overall low quality of the body of evidence was found in the present systematic review. Paper
IV provides further information on the main findings and quality of the body of evidence for
each result.
Discussion
Summary of Main Findings
This feasibility study showed that a high intensity interval exercise program starting two weeks
after surgery in patients with NSCLC was safe and feasible. Recruitment of NSCLC patients to
the rehabilitation intervention, with a focus on exercise, was challenging. The preoperative
home-based exercise was found to be inconsistent and not feasible in a set-up where the time
interval between referral and surgery (fast-track surgical program) was restricted to 14 days
54
(Paper II-III). The systematic review showed that exercise improved exercise capacity and the
physical component of HRQoL in the short-term, but no beneficial effect was found in the
mental component of HRQoL. In the systematic review, it was not possible to draw conclusions
about the effect of early-initiated postoperative exercise compared to late-initiated exercise due
to the lack of well-conducted RCTs (Paper IV).
Safety
This feasibility study is the first study of its kind to initiate supervised high intensity interval
exercise, in a non hospital setting, two weeks after surgery for NSCLC. The feasibility study
demonstrated that the intervention was safe since no serious adverse events or other adverse
events occurred during the intervention period. Only a few studies have initiated exercise
interventions within two weeks after operation for NSCLC, and none of them included
registration of adverse or serious adverse events (127,134–136). However, all of these studies
were conducted in a hospital setting and none of these study prescribed high intensity interval
exercise and the intervention was performed once daily (high to moderate intensity) from the
first postoperative day until discharge from hospital (127,134,135). One study initiated an
exercise intervention four days after discharge from hospital but the intervention were
characterized as being home-based and unsupervised (136). In a feasibility study by Jones et al
(2007), patients with NSCLC were recruited at least three weeks post surgery, with a mean of
around 30 days after surgery, and the intervention consisted of high intensity cardiovascular
exercise (64). This study stands out by reporting safety in relation to exercise and found neither
adverse events nor serious adverse events in connection with the exercise (64).
High intensity interval exercises are shown to be superior to moderate intensity continuous
exercise when it comes to inducing health benefits in healthy individuals (137). Due to this
benefit and the safety of high intensity interval exercises in healthy individuals, this type of
exercise has emerged in clinical populations, such as patients with DM (137). The acute cardiac
response to high intensity interval exercise has been assessed in patients with coronary heart
disease and no contraindications to high intensity interval exercise were observed (138,139).
Also, in heart transplant recipients who completed an eight-week high intensity interval exercise
program, the results showed significant improvements in cardiorespiratory capacity without
adverse events occurring during the study (146). Notably, all patients in the studies mentioned
above underwent a full medical screening and cardiopulmonary exercise test prior to
participation (138–141). At the same time, it is important to stress that for patients with a recent
55
bypass surgery, the test was performed >3 months after the surgical procedure, and for heart
transplant patients, >1 year post-transplantation, ensuring sufficient time for wound healing after
a major surgical procedure.
Recent guidelines on physical activity and exercise for cancer survivors have not clarified the
optimal time for initiation of exercise (78,104). For many years in the Danish health care system,
the general practice has been to postpone initiation of any type of exercise, apart from
mobilization, to six weeks after cancer surgery to allow sufficient time for wound healing. No
evidence has been presented, however, to support this recommendation and the judgment of how
early it is safe for a patient to start exercising after lung surgery often depends on the surgeon in
charge. ACSM guidelines for cancer survivors state, quoted in Schmitz et al (2010), p. 1413:
“Allow adequate time to heal after surgery. The number of weeks required for surgical recovery
may be as high as 8 weeks” (142).
In 2007, Danish legislation specified that the local authorities were responsible for the
rehabilitation of patients, including cancer patients, a task previously undertaken by hospitals
(72). Since the aim of rehabilitation is to restore patients to the optimal level of functioning in
their community and homes, it thus appears logical to perform rehabilitation in the patient’s
immediate environment (143). Research has indicated that community-based rehabilitation can
be just as beneficial for patients as hospital-based rehabilitation (144,145). Some of the safety
concerns about cancer patients doing high intensity interval exercise in a non-hospital setting is
the lack of access to blood samples, medical records and assistance in an emergency.
The ACSM guidelines for cancer patients state that prescribing exercise should be individualized
according to pretreatment aerobic fitness, medical comorbidities, response to treatment and the
immediate or persistent negative effects of treatment experienced at any given time (142).
Previous studies in cancer patients during chemotherapy found that screening before exercise has
a positive impact on the patients’ sense of safety during exercise (79,80).
In this feasibility study, every patient was screened prior to inclusion by the primary surgeon in
accordance with the inclusion criteria. Additionally, a specialized cancer nurse and
physiotherapist were in charge of the exercise sessions and the patients were screened prior to
every exercise session for physical capability (see methods section). The completed screening
did not result in any omission of patients from participating in the exercise sessions, which
theoretically could have prevented serious adverse events or adverse events.
In healthy individuals, the health benefits of physical activity are well documented (147), even
though recent research also indicates that exercise induces an acute risk of serious adverse events
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(147). This evidence also indicates, however, that the health benefits of routine physical activity
by far outweighs the acute risk of serious adverse events (146). The acute risk is actually found
to decrease with increased levels of physical activity, such that highly active individuals appear
to have the lowest risk (two to five-fold lower). The incidence of adverse cardiovascular events
in healthy individuals is below 0.01 per 10,000 participant hours (147). The transferability to
lung cancer patients is unknown, but as many lung cancer patients are current or former smokers,
they often have cardiovascular comorbidities, such as hypertension (38% in this study),
dyslipidimia (23%) or atherosclerosis (unreported). Furthermore, 20% of the patients included
had COPD. This feasibility study did not exceed a total of 1000 exercise sessions, which is why
the risk of lung cancer patients experiencing a cardiovascular event is difficult to calculate in the
same way as with healthy individuals.
Postoperative Complications
This feasibility study showed that initiating high intensity interval exercise two weeks after
surgery for NSCLC does not increase or decrease the incidence of postoperative complications
compared to the group with late-initiated exercise. Postoperative pulmonary complications
following lung resection are associated with longer length of hospital stay, higher rate of
intensive care unit admissions, higher 30-day readmissions and reduced overall survival,
depending of the degree of resection (148–150), which is why prevention is of great importance.
The ability to reduce postoperative pulmonary complications is of significant value to patients
and to the healthcare system. A recent Cochrane review showed that in patients with operable
lung cancer, preoperative exercise decreased the risk of postoperative pulmonary complications
by 63%, reducing both intercostal catheter duration (by three days) and length of hospital stay
(by four days), and also improved preoperative exercise capacity and FVC in patients
undergoing lung resection (53). The Cochrane review stressed that the findings have to be
interpreted with caution due to differences between the studies and small sample sizes.
The same review found a number needed to treat for a beneficial outcome of four, which means
that for every four patients performing preoperative exercise, one less patient will develop a
postoperative pulmonary complication (53). In the PROLUCA feasibility study, only three out of
12 patients managed to exercise daily prior to surgery in a fast-track setting, which is why it is
not possible to draw a conclusion about the effect of preoperative exercise on the incidence of
postoperative complications.
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Recruitment
The recruitment rate was 32% of the eligible patients, and the primary reason for them not
attending was either logistical problems or concerns about their upcoming surgery. Similar
exercise studies in patients with NSCLC show diversity in regards to the percent of recruited
patients. Some studies report recruitment rates that are comparable to the one found in this study
(64,128). Other studies report a much higher recruitment rate of around 65-80% (65,127), while
the rate can also be found to be much lower, around 11% (54,134). How recruitment rates are
reported, however, differs between the studies, as some reported patients out of eligible patients
and others reported patients out of patients being assessed for eligibility (54,64,65,127,128,134).
Logistical problems are one of the reasons often reported as a barrier to participation in
rehabilitation (134). In research on cardiac rehabilitation, barriers to participation in
rehabilitation program are categorized in three ways (151): 1) patient factors (e.g., lack of
interest, lack of support from friends and family, reluctance to change lifestyle); 2) service
factors (e.g., cost and reimbursement, location and accessibility, car parking); and 3) professional
factors (e.g., knowledge and attitudes, referrals and prejudices) (151). The same barriers have
been observed in the recruitment process in this feasibility study.
Adherence to the Preoperative Exercise
The stated hypothesis that preoperative home-based exercise is safe was supported since no
serious adverse events were found. It could not be confirmed, however, that preoperative home-
based exercise is feasible in patients with operable lung cancer, since adherence to the
preoperative home-based exercise was inconsistent due to the short time interval between
referral and surgery (fast-track surgical program). To our knowledge, not many studies have
assessed the effect and adherence of a home-based exercise program prior to resection in patients
with NSCLC being treated in a fast-track setting similar to the two weeks in this feasibility
study. One study found good adherence to a four-week home-based preoperative exercise
intervention as all of the included patients (n=16) completed more than 75% of the prescribed
exercise sessions (152). Apart from the time difference between a four-week and this two-week
exercise program, the patients included in the study by Coats et al (2013) were younger and
diagnosed with early-stage lung cancer, compared to the patients included in this feasibility
study (152). In Denmark, the maximum waiting time for lung cancer surgery is, by law, specified
not to exceed two weeks. As a result, a four-week preoperative exercise program would not
actually be possible in a Danish setting. The four-week preoperative waiting time until surgery
58
for lung cancer in the Canadian study by Coats et al (2013) brings into consideration that the
difference between two and four weeks from diagnosis to surgery might not be that crucial. It
could be interesting to investigate if similar survival rates for patients with NSCLC are found in
countries where the preoperative waiting time is four weeks in stead of two weeks in Denmark.
And also to examine if preoperative exercise intervention could have a positive impact on
survival.
Preliminary evidence suggests that a high exercise capacity at the time of diagnosis of NSCLC is
related to extended survival, but this has to be examined further (57,153). The postulated
mechanism linking exercise with prolonged survival in lung cancer is the influence of exercise
on the regulation of sex hormones, insulin/IGF and inflammatory markers (154). In addition,
research on mice has investigated the mechanism that may link physical activity and exercise to
cancer control and this research is of great importance to eventually recommending exercise as
medicine for patients with cancer (155,156). Despite promising results with regards to
preoperative exercise in NSCLC patients and its reduction of postoperative complications,
Cavalheri & Granger’s (2017) systematic review rates the quality of evidence as low and
highlights the need for further RCTs to investigate the effect of preoperative exercise on
mortality and the cost/benefit of this intervention (53).
Adherence to Postoperative Exercise
The feasibility study confirmed the stated hypothesis, i.e., that high intensity interval exercise, in
a non-hospital setting, initiated two weeks after surgery in NSCLC patients was feasible. The
average onset of exercise was 18 days (range 13-29) post surgery in the early intervention group
and 47 days (range 22-80) in the late intervention group. Despite several strategies to enhance
adherence to the exercise sessions, 11 patients dropped out during the intervention, five patients
(45%) from the early intervention groups (group 1 and 3) and six patients from the late
intervention groups (group 2 and 4). The primary reason for dropping out was either lack of
motivation to complete (n=4) or side effects from the adjuvant chemotherapy (n=3).
Seventy-three percent of patients in the feasibility study completed the supervised group
exercise, which is comparable to other exercise studies in patients with NSCLC, where the
average percentage of patients who completed the study was around 80% (64,65,127–129).
Although 73% of the lung cancer patients completed the group exercise, only 52% of them
attended >70% of the sessions and 48% <70% of the group sessions. In other studies, the lung
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cancer patients varied and the attendance rates are not described, making it impossible to
calculate comparable rates (64,65,127–129).
According to Kamshoff et al (2014), high attendance rates in patients with different cancer
diagnoses were defined as attending at least 80% of the sessions, and the effect of RCTs
evaluating exercise programs depends largely on patients’ participation or exercise adherence
(68). In this feasibility study, only 13 patients (33%) received chemotherapy. Due to the low
number of patients, it is not possible to describe the barriers to participation in exercise. Three of
the eleven dropouts, however, stated the reason to be side effects from adjuvant chemotherapy,
which is why rehabilitation programs must focus on strategies to maintain exercise during
treatment. A study in cancer patients found that high levels of fatigue and no previous experience
with exercise influenced participation in exercise trials (68). Furthermore, minimizing practical
barriers to participation, such as travel distance and flexible exercise schedules, were suggested
in cardiac rehabilitation as promising strategies to enhance participation in future studies (151).
Cardiorespiratory Capacity
This feasibility study showed a trend towards a mean decrease in fitness of 1.9 mL/kg/min (95%
CI: -3.9 to 0.2, p=0.0741) from baseline to post intervention and this decrease was retained at 1.8
mL/kg/min (95% CI: -3.7 to 0.11, p=0.0637) at one-year follow-up. Since this feasibility study is
underpowered, the results must be interpreted with caution. Contrary to these findings, other
studies investigating the cardiorespiratory effect of high intensity exercise in patients resected for
NSCLC show an increase in fitness (61,62).
An RCT study found a between-groups difference of 3.4 mL/kg/min (95% CI 1.3 to 5.5 and p-
value at 0.002) in favor of the exercising group (65). The baseline assessment was collected post
surgery, which eliminates the impact of surgery on the exercise capacity measured. This is in
contrast to this feasibility study, where the baseline assessment was measured within two weeks
prior to surgery, which is also the case in other exercise studies measuring cardiorespiratory
capacity in patients resected for NSCLC (132,157). It is therefore difficult to distinguish between
the impact of the surgery and the exercise intervention. In addition, Edvardsen et al (2014) used
a cardiorespiratory exercise protocol involving walking on an uphill treadmill, which might be
more appropriate for use in patients resected for NSCLC (65).
A Canadian study in patients with breast cancer showed a 17% difference in cardiorespiratory
capacity in favor of an uphill treadmill VO2max test compared to a cycling VO2max test (158).
The study by Dolan et al (2012) found that experience and local muscular fatigue may have been
60
limiting factors during the cycling protocol rather than central fatigue of the cardiorespiratory
system, thereby presenting an inaccurate level of cardiorespiratory capacity (158). Cycling
requires a different skill than walking and in the study by Dolan et al (2012) they speculate, that
the lack of experience in cycling influences the results (158). In Denmark the situation is
different, as cycling is integrated in daily life and the general population are using bikes as a
vehicle. Still it is not known if a treadmill is more appropriate for use in patients with NSCLC,
with the intention to avoid local muscular fatigue before a central fatigue constrains further
participation in the test.
An improvement in VO2peak of 15% is generally accepted as a clinically important change in
healthy individuals but in lung cancer, an improvement of 11% may in fact be meaningful,
especially in the context of severe deconditioning and high postsurgical morbidity (64). Data
from this study does not indicate whether the fitness level was even lower immediately after
surgery and thereafter increasing slowly over time. The starting point for the evaluation of the
effect of training on cardiorespiratory capacity is not measured immediately before initiation of
the exercise intervention, which is why this value may be lower than the value measured at
baseline prior to surgery. This will result in an underestimation of the effect of the exercise
intervention.
Another important difference between the study mentioned and this study is the duration of the
intervention period and frequency of exercise sessions. In this Danish study, two exercise
sessions every week for 12 weeks were chosen, which is used very commonly in the
rehabilitation of patients with a variety of diagnoses, but in Edvardsen et al’s study (2014), they
exercised three times a week for 20 weeks (65).
HR data showed that the patients in the present feasibility study were able to exercise with an
intensity that was even higher than prescribed. In the first four weeks of the 24 sessions, the
intensity of the cardiorespiratory exercise was 74% (SD 8) of individually determined HRmax
(intended to be ~50-60%) and for the last eight weeks it was at 77% (SD 4) of individually
determined HRmax (intended to be ~70-90%).
Muscle Strength
Results on muscular strength showed a significant improvement for patients exercising for at
least 70% of the sessions. This improvement was found to be 30 kilos on the leg press (95% CI:
5 to 55, p=0.0220) and five kilos on the chest press (95% CI: 2 to 8, p=0.0029), measured post-
intervention. Comparably, Edvardsen et al (2014), found a baseline mean in the intervention
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group of 131.9 (SD±45.7) kilos on the leg press and a post-intervention mean of 159.3
(SD±48.4) kilos (65). Hence the improvement in this feasibility study is also found in other
similar studies in patients resected for NSCLC, but diversities in the methods of measuring
muscular strength makes it difficult to compare the results (127,159). The improvement is of
great importance as muscle strength is inversely associated with all-cause mortality (160). Loss
of muscle strength, a common occurrence in the elderly, is associated with increased mortality
independent of age or other clinical and functional variables (160). Furthermore, research has
shown that cancer patients have significant impairments in muscle strength regardless of disease
stage when compared with healthy controls matched by age, sex, body mass index and/or
physical activity level (161). Based on this, performing strength exercises is recommendable for
not only lung cancer patients but for all patients with cancer.
Walking Distance
In this thesis, data on 6MWD showed a significant and clinically relevant increase of 28 meters
(95% CI: 4 to 51 and p=0.0229) from a baseline of 495 (SD +63) meters to post-intervention for
patients who participated in at least 70% of the sessions. Another study in the same group of
patients found a 43% improvement in 6MWD after the intervention, but the baseline measured
up to three months after surgery was only 351 meters (interquartile range: 240-436) (162). This
indicates that the patients in the study by Spruit et al (2006) had a lower physical capacity at
baseline than the patients in the PROLUCA feasibility study (162). In another study, Brocki et al
(2014) found a decrease in walking distance to 76% of the preoperative values at day five post
surgery in patients with NSCLC, while two weeks after surgery there was a partial recovery at
93% of preoperative values (128). The feasibility study measured the baseline prior to surgery,
which is why it would be expected that the true baseline value before the exercise intervention is
lower than the value measured preoperatively and that the subsequent increase would be
correspondingly higher.
The 6MWD is the most widely used non-laboratory test to measure functional capacity in
individuals with chronic lung disease, including those with lung cancer and COPD (54,87).
Recent research estimated the MID for a deterioration of 6MWD in patients with lung cancer to
be between 22 m and 42 m, or a change of 9.5%, which is consistent with the MID established in
COPD populations (163,164). In sum, the three sections above verify the stated hypothesis that
improvement in physical capacity in patients following surgery for lung cancer is achievable,
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since improvements were found in muscular strength and in 6MWD but not in cardiorespiratory
capacity.
HRQoL Outcomes
Overall, this feasibility study verifies the stated hypothesis that HRQoL improves significantly
during the study period, from around two weeks prior to surgery until one year after surgery, in
patients with NSCLC participating in an exercise intervention. This was demonstrated by the use
of various validated patient-reported outcomes (see Table 1).
Results from FACT-L measurements showed that the total score improved significantly during
the study (p= 0.0163) from a mean baseline score of 105 (95% CI: 99 to 112) to the highest
reported level, a mean score of 114 (95% CI: 109 to 120), measured six months after surgery.
The level of LCS (subscale in FACT-L) increased significantly (p= 0.0421) from a baseline
score of 21 points (95% CI: 19 to 22) to the highest mean score, measured one year post surgery,
of 23 (95% CI: 22 to 24). A high LCS score indicates a low level of symptoms and, as it has
previously been demonstrated that a two to three point improvement in LCS is a clinically
meaningful change in patients with NSCLC, the results are interpreted an inprovement as such
(165).
Results from the EORTC-QLQ-C30 showed that global QoL improved significantly (p=0.0032)
during the study from a mean baseline value of 65 (95% CI: 57 to 74) to the highest mean value
measured six months post surgery of 82 points (95% CI: 75 to 88), which is nine points higher
than the score in an age-matched Danish cohort in healthy individuals (mean score 73 +SD 23)
(113). Braun et al (2011) found that in patients resected for NSCLC, a 10-point increase in
global QoL was associated with a 9% increase in survival (166). A difference of five to 10 points
represents a small but clinically meaningful change, 10 to 20 points a moderate change and more
than 20 points a larger clinically meaningful change seen from the patient’s perspective (167).
As a result, the improvement found in this feasibility study can be interpreted as a significant and
moderate clinically important change. However, the findings of the present feasibility study must
be interpreted with caution since the lack of a control group weakens any conclusion regarding
the effect of this intervention.
Additionally, results from the SF-36 found that the mental health component score improved
significantly during the study period (p=0.0004) to a mean level of 53 points (95% CI: 49 to 58)
measured at both the six-month and one-year follow-up. These findings are one point below the
mean mental health component score in an age-matched random sample of 6000 individuals
63
drawn from the Danish Civil Registration System (114), which is in contrast with recent findings
in a Danish RCT on operable lung cancer patients, where a significant improvement in the
mental health component score was not found (157). This is in contrast to this study, where the
mental health component score improved significantly and stayed unchanged at one year follow-
up.
The same study by Brocki et al (2014), however, found an improvement in the SF36 physical
health component score, with a difference between the intervention group and the control group
of 3.76 points (95% CI: -0.1;7.62, p=0.06) in favor of the intervention group (128), as well as in
the baseline values measured approximately three weeks after surgery. Brocki et al’s study
(2014) found that the tendency toward improvement in the physical health component score
post-intervention was reversed 12 months after surgery, where the control group presented
slightly better measures overall (128). In this thesis, there was, however, a decrease from
baseline measured preoperatively to one year after surgery in the physical health component
score, but the results were not significant (p=0.5327) (results not presented). Again, the impact of
surgery does not indicate whether the physical health component score had been even lower
immediately after surgery and thereafter increased slowly over time.
Changes in Smoking, Alcohol and Physical Activity Habits
Results from the feasibility study showed that smoking and alcohol habits decreased, leading to
fewer smokers and fewer patients with an alcohol intake above the recommended amount of <7
units per week for women and <14 for men, in the period from baseline to post-intervention.
This effect, however, reversed one year after surgery without reaching the baseline. The level of
sedentariness dropped from 15 to 4% during the intervention period. The changes in smoking,
alcohol and physical activity habits were not statistically significant, but the results are of clinical
importance and underline the need for optimizing maintenance of lifestyle changes after
rehabilitation.
Research in patients with NSCLC found that 40% of them did not meet physical activity
recommendations measured at the time of diagnosis and six months after unless they were
participating in a specific exercise intervention (55). Furthermore, after six months, the same
patients had a decline in physical activity, functional capacity and strength compared to healthy
individuals. This is further confirmed by another study showing that NSCLC patients had
postoperatively longer periods of sedentary behavior than healthy controls (168).
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Effect of Early Postoperative Exercise
Results from the meta-analysis showed that postoperative exercise interventions improved
exercise capacity (SMD 0.48; 95% CI 0.04 to 0.93) and the physical component of HRQoL
(SMD 0.50; 95% CI 0.19 to 0.82) in the short-term, but no beneficial effect was found on the
mental component of HRQoL. Only a single study has evaluated the long-term effect and
showed no effect on either physical capacity or HRQoL (128). These findings are comparable to
the findings in a previous systematic review, where the exercise capacity was significantly
higher in the intervention group compared to the control group (MD 50 m; 95% CI 15 to 85 m)
(49). This systematic review included RCTs with different measures of exercise capacity or
HRQoL, which is why comparing the results in the calculated SMD was difficult. The Cavalheri
et al’s systematic review (2014), found no significant difference in HRQoL between the
intervention and the control groups (SMD 0.17; 95% CI -0.16 to 0.49), contrary to the findings
in this systematic review, which might be due to diversity in the design. Cavalheri et al (2014)
included studies with various designs that included a few RCTs, only one of which met the
inclusion criteria of the review in this thesis. In addition, two new RCTs with a total of 131
patients were included. Another difference between other systematic reviews, including
Cavalheri et al (2014) and this systematic review, is the inclusion of studies dealing with both
pre and postoperative exercise (49,61,169,170).
This systematic review is the first of its kind to examine the effect of postoperative exercise in
patients with NSCLC after lung resection, including solely RCTs and with postoperative
outcome measurements only included. In this way, the impact of the surgery is eliminated from
the effect of the intervention, but one may expect lower baseline assessments postoperatively,
due to sequelae to the operation, as compared to levels measured preoperatively. Other previous
systematic reviews confirmed that both pre and postoperative exercise was associated with
positive results for exercise capacity and some HRQoL domains (49,61,169,170). The quality of
the evidence provided by the RCTs included in the meta-analysis has been rated, according to
GRADE, as low or very low, mainly because of some serious risks of bias, inconsistency in
effect estimates and imprecision, as the small sample sizes caused wide CIs. Consequently, the
results of this review must be interpreted with caution.
The systematic review in this thesis could only identify sparse research that encompasses
knowledge about the influence of early initiation of exercise after lung cancer surgery. Only one
study initiated the exercise intervention within two weeks following surgery, which is why it is
not possible to evaluate whether or not early-initiated exercise will improve the effect of exercise
65
capacity and HRQoL. As a result, the study contained a home-based non-supervised training
program following discharge, which potentially could have lowered adherence to the
intervention, reducing its effect (127). Accordingly, hypothesis number four could not be
confirmed. Despite the fact that no effect could be found, an early-initiated intervention could be
beneficial due to several reasons. One is the reduction of the postoperative period with inactivity
and research from cardiac rehabilitation shows favourable effects of exercise initiated in the
acute phase following myocardial infarction when compared to late onset of exercise (171).
One study has shown that exercise may facilitate wound healing via neuroendocrine regulation
among healthy older adults participating in an exercise intervention compared to a control group
(172). Therefore, exercise may also have beneficial effects on patients recovering from a lung
resection since wound healing is found to be accelerated.
Methodological Considerations
A methodological concern is the chronology of studies in the papers included in the thesis, which
at first might appear as a reversed way of doing traditional clinical research. A classic approach
would start out with a systematic review, followed by a feasibility study and leading to an RCT,
but the research approach always depends on the research question being asked (173). This
thesis, started out with a concept paper describing the intended PROLUCA RCT study. Due to a
low recruitment rate in a surgical fast-track setting for operable lung cancer patients, the
preoperative exercise intervention was judged to be problematic. The decision was consequently
made to shift from an RCT to a feasibility study investigating the original perioperative design
on a smaller scale while simultaneously changing the focus from effect to safety and feasibility.
Another methodological concern is the lack of a postoperative assessment performed
immediately before initiation of exercise. This could have revealed a more precise result of the
intervention, since the impact of the surgery would be isolated. This approach would require
taking into account the choice of cardiorespiratory exercise tests since it has not yet been
clarified whether it is safe to perform a maximum performance test two weeks after surgery in
patients undergoing thoracic surgery.
Another methodological concern is that a feasibility study is not designed to evaluate the effect
of the intervention but instead is meant to evaluate safety and feasibility. Moreover, a feasibility
study includes a small sample size, which is why the use of statistical tests may be problematic
because of the risk of finding or not finding statistically significant results. Therefore, results
from a feasibility study must be interpreted with caution.
66
Strengths and Limitations
This thesis has several limitations, one of which is the low recruitment rate in the feasibility
study, which could possibly result in a selection bias and perhaps indicate that the intervention
was only feasible in a selected group of NSCLC patients as the population included might not be
representative of the population of patients undergoing surgery for NSCLC. Further on, the
selection bias could influence the options available for implementing these results in a clinical
setting. It might be that the patients choosing to participate in the present study represent a group
with better physical fitness than the group not participating in the study. Unfortunately, it has not
been possible to collect data on the patients eligible for the study but not included, although it
could have been of great value to compare participants and non-participants with regards to
demographics, smoking status, presence of comorbidity and pulmonary function. A comparison
of the patients included in this feasibility study with cohort studies in patients with NSCLC
reveals similarities regarding age, sex, pulmonary function and comorbidities (174,175).
Another limitation is the quality of the smoking information in this feasibility study, which only
reports years of smoking and not the intensity. A more precise way of reporting the exposure to
tobacco is pack-years of smoking (176), which is calculated by multiplying the average number
of packs of cigarettes smoked per day (intensity) by the number of years the person has smoked
(176). This method is widely used within the health care system.
One of the strengths is that the study was conducted in a municipality, which has been legally
responsible for the rehabilitation of various patient categories since 2007. This strengthens the
applicability of the intervention to general clinical practice. The rehabilitation systems for cancer
patients in Nordic countries (Denmark, Norway, Finland, Sweden, Iceland, Germany and the
Netherlands) are based on a similar, multidimensional and multidisciplinary understanding of
cancer rehabilitation (72), which also enhances the transferability of the results.
Another strength is the comprehensive literature search on lung cancer and exercise carried out
by two review authors that resulted in sufficiently identifying relevant studies and successfully
obtained missing data. Additionally, the investigative effort put into finding on-going or
unpublished studies improved the probability that all relevant studies were found. This was done
by searching trial registrations and contacting recognised authors in the research field. The
language criteria for exclusion may have limited the inclusion of additional studies. The three
studies excluded due to missing data also represent a limitation, as their effect estimates could
have influenced the results of this review.
67
Conclusion
This thesis showed that early, supervised, group-based high intensity interval exercise is both
safe and feasible in patients with operable NSCLC. High intensity interval exercise, in a non-
hospital setting, initiated two weeks after lung resection was achievable. The preoperative home-
based exercise was not feasible in the present setting due to the short time interval between
referral and surgery. Results from the feasibility study showed that HRQoL and muscle strength
improved significantly during the study period, from time of diagnosis until one year after
resection in patients with NSCLC participating in rehabilitation.
Results from the systematic review also showed that exercise interventions for patients resected
for NSCLC improved exercise capacity and the physical component of HRQoL in the short-
term, based on results from a meta-analysis. Due to the lack of well-conducted RCTs, it was not
possible draw any conclusions about the effect of early-initiated postoperative exercise compared
to late-initiated exercise.
Perspectives
Inactivity in lung cancer patients is known to be associated with worse outcomes in HRQoL and
symptom burden (177). The challenges experienced in recruiting lung cancer patients to the
exercise intervention in the feasibility study is not a unique issue related to lung cancer but a
general challenge in the field of clinical research on rehabilitation (178). This recruitment issue
should not prevent further research within this area since the consequences of being sedentary
are critical (146), especially in lung cancer patients. With the significant cancer burden and
rising cancer costs, rehabilitation is still an inexpensive cancer therapy (179).
Supplementary qualitative research in preoperative exercise for NCSLC patients highlights the
need for psychosocial support during the period from diagnosis to surgery, which also supports
the idea of some kind of a preoperative intervention (180). Therefore, future research should
continuously focus on how to motivate and encourage lung cancer patients in all stages, as well
as lung cancer survivors, firstly, to stop smoking and, secondly, to be more physically active
(179). Additionally, research that identifies how to motivate subgroups of lung cancer patients
that are at greater risk of remaining sedentary during and after treatment is warranted (178).
Discovering that high intensity interval exercise is safe in patients two weeks after surgery for
lung cancer is important since it might prevent physical inactivity in the postoperative period and
68
this could potentially lead to a better outcomes in physical capacity and HRQoL in both the short
and long-term, which previous research indicates is affected in operable lung cancer patients
(49). The results of PROLUCA RCT II will reveal the actual effect of an early exercise
intervention initiated two weeks after surgery compared to a late-initiated exercise intervention
in patients with operable lung cancer based on the parameters physical capacity and HRQoL. As
a result, this thesis, in combination with the PROLUCA RCT II study, will add valuable
knowledge to the quest for finding the best rehabilitation methods for patients with NSCLC.
The Danish health care system has another challenge not covered by this thesis, but still
important for the patients. Lung cancer incidence is found to be inversely associated with
educational, occupational and income-based socioeconomic status regardless of adjustments for
smoking (181). Thus, even in the Danish health care system, which has free, equal access to
health services, disadvantaged groups are less likely to receive rehabilitation services (182).
Additionally, another Danish study found that early-stage NSCLC patients who lived alone and
had a low income were less likely to undergo surgery compared to those who had a high income
or who lived with a partner, even after control for possible explanatory factors (183). Research in
lung cancer and socioeconomic status underlines the need for efforts to ensure optimal treatment
of lung cancer patients with a low social status (184). This thesis thus also bolsters arguments for
ensuring that all lung cancer patients are referred to rehabilitation regardless of their social
status.
69
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Appendices
Paper I
Paper II
Paper III
Paper IV
Sommer et al. BMC Cancer 2014, 14:404http://www.biomedcentral.com/1471-2407/14/404
STUDY PROTOCOL Open Access
Perioperative rehabilitation in operation for lungcancer (PROLUCA) – rationale and designMaja S Sommer1*, Karen Trier1, Jette Vibe-Petersen1, Malene Missel2, Merete Christensen2, Klaus R Larsen3,Seppo W Langer4, Carsten Hendriksen5, Paul Clementsen6, Jesper H Pedersen2 and Henning Langberg7
Abstract
Background: The purpose of the PROLUCA study is to investigate the efficacy of preoperative and earlypostoperative rehabilitation in a non-hospital setting in patients with operable lung cancer with special focus onexercise.
Methods: Using a 2x2 factorial design with continuous effect endpoint (Maximal Oxygen Uptake (VO2peak)), 380patients with non-small cell lung cancer (NSCLC) stage I-IIIa referred for surgical resection will be randomly assignedto one of four groups: (1) preoperative and early postoperative rehabilitation (starting two weeks after surgery);(2) preoperative and late postoperative rehabilitation (starting six weeks after surgery); (3) early postoperativerehabilitation alone; (4) today’s standard care which is postoperative rehabilitation initiated six weeks after surgery.The preoperative rehabilitation program consists of an individually designed, 30-minute home-based exerciseprogram performed daily. The postoperative rehabilitation program consists of a supervised group exercise programcomprising cardiovascular and resistance training two-hour weekly for 12 weeks combined with individualcounseling. The primary study endpoint is VO2peak and secondary endpoints include: Six-minute walk distance(6MWD), one-repetition-maximum (1RM), pulmonary function, patient-reported outcomes (PROs) on health-relatedquality of life (HRQoL), symptoms and side effects of the cancer disease and the treatment of the disease, anxiety,depression, wellbeing, lifestyle, hospitalization time, sick leave, work status, postoperative complications (up to30 days after surgery) and survival. Endpoints will be assessed at baseline, the day before surgery, pre-intervention,post-intervention, six months after surgery and one year after surgery.
Discussion: The results of the PROLUCA study may potentially contribute to the identification of the optimalperioperative rehabilitation for operable lung cancer patients focusing on exercise initiated immediately afterdiagnosis and rehabilitation shortly after surgery.
Trial Registration: NCT01893580
Keywords: Cancer, Rehabilitation, Exercise, Lung cancer, NSCLC
BackgroundLung cancer is one of the most frequently occurringcancer diagnoses with the highest mortality rate [1].Lung cancer is divided into Small-Cell Lung Carcinoma(SCLC) and Non-Small Cell Lung Carcinoma (NSCLC).Surgery is at present the primary treatment for NSCLC.According to the Danish Register of Lung Cancer 2011,the 2-year survival was 62% and the 5-year survival 42%
* Correspondence: [email protected] Centre for Cancer and Health, Municipality of Copenhagen,Nørre Allé 45, DK-2200 Copenhagen, DenmarkFull list of author information is available at the end of the article
© 2014 Sommer et al.; licensee BioMed CentraCommons Attribution License (http://creativecreproduction in any medium, provided the or
following radical surgery for lung cancer [2]. Modernsurgical treatment includes both minimal invasive sur-gery, e.g. video-assisted thoracoscopic surgery (VATS),and open surgery such as thoracotomy. An increasingproportion of lung cancer patients are operated by VATStechnique in both Europe and the US. At CopenhagenUniversity Hospital (Rigshospitalet), more than 60% ofall lung cancers patients are operated by VATS [2].Improved surgical techniques combined with effective
adjuvant chemotherapy have led to a significant survivalbenefit in individuals with NSCLC [3,4]. Postoperativecomplications are experienced by 25% of the patients
l Ltd. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andiginal work is properly credited.
Sommer et al. BMC Cancer 2014, 14:404 Page 2 of 10http://www.biomedcentral.com/1471-2407/14/404
with NSCLC [2], and the risk of developing postopera-tive complications during the first two weeks after sur-gery has been reported to be dependent on differentfactors, e.g. preoperative cardiorespiratory capacity, mea-sured as VO2peak [1,5]. The physiological consequencesof ageing and inactivity combined with the cancer dis-ease and the treatment of cancer result in a marked re-duction in VO2peak and functional capacity [6-8]. Otherfactors such as smoking [9], alcohol consumption [10],nutritional status [11] and comorbidity [12] are predic-tors of postoperative complications. The treatment ofNSCLC and other types of cancer is complex and poten-tially lethal. Accordingly, side effects are now recognizedas a subject of major clinical importance [13]. The sideeffects may comprise physical and psychological as wellas social distress with symptoms such as reduced cardio-respiratory capacity, paresthesia, post-thoracotomy painsyndrome, fatigue, anxiety, and depression [14-16]. Thelate side effects are long-lasting or even chronic andmay result in restrictions in activity of daily living andreduced quality of life [5,17-23].A Cochrane systematic review from 2012 indicates
that exercise in patients with a variety of cancer diagno-ses may have beneficial effects on HRQoL [24]. This issupported by a Danish randomized controlled trial with269 cancer patients (different diagnoses) according towhich patients receiving chemotherapy tolerate intensivephysical exercise and experience reduced fatigue, depres-sion, and nausea [25]. In general, rehabilitation in cancerpatients based on physical exercise perioperatively hasbeen shown to increase HRQoL and physical activity,and at the same time reduce the side effects of the treat-ment [24,26-33]. There is consistent evidence from 27observational studies that physical activity is associatedwith reduced all-cause, breast cancer-specific, and coloncancer-specific mortality [34].Clinical studies of preoperative physical exercise in
patients with operable NSCLC are sparse. However, arecent prospective feasibility study on 25 patients withNSCLC reports that the patients tolerate 30 minutes ofpreoperative intensive cardiovascular exercise 5 times/week. The study finds that exercise significantly improvesVO2peak and 6MWD [35]. Two other studies indicate thatrehabilitation including preoperative exercise can im-prove physical and psychological outcome in patientswith NSCLC [36,37].The effect of postoperative physical exercise in patients
with lung cancer has been investigated briefly. The studiesdiffer in type of intervention, dose and timing of interven-tion, and the research is primarily based on case studiesand studies with few and heterogeneous participants[36]. Two non-randomized feasibility studies observedthat supervised moderate to high intensity cardiovascu-lar exercise initiated four weeks after surgery is safe and
feasible for operable lung cancer patients. The interven-tion consisted of three weekly cycling sessions for aperiod of 14 weeks, and participation was associatedwith a significantly improved HRQoL [38,39].In a prospective study of 45 lung cancer patients, exer-
cise on ergometer bikes 30 minutes daily, initiated twoweeks after end of cancer treatment (including both sur-gery and chemotherapy), was reported to result in a pro-nounced improvement in exercise capacity and functionalstatus [40]. The results are confirmed by other studies[41,42]. Another randomized study of 53 lobectomizedlung cancer patients showed retention of muscle strengthin the intervention group in which the patients partici-pated in mobilization and strength exercise twice dailyduring admission followed by a 12-week long home exer-cise program. HRQoL (EORTC questionnaire) and phys-ical capacity (measured by 6MWD) were unchanged [43].Overall, these studies indicated that postoperative exercisemay have a positive effect on physical capacity andHRQoL in NSCLC. A systematic review from 2011 con-cluded that pre- and postoperative exercise is safe andfeasible for NSCLC patients and associated with a positiveeffect on physical capacity and, to some extent, HRQoL[26]. However, the main part of the studies quoted in thereview are small case series and the only randomizedstudy in the review observes no difference between theintervention and the control group [26]. In summary, sev-eral studies indicate that postoperative exercise of NSCLCpatients is safe and associated with improvement of fitnessand self-reported outcome such as HRQoL and fatigue[27,44]. Positive effects of perioperative exercise interven-tions are more pronounced with moderate- to vigorous-intensity versus mild-intensity exercise programs. Moreresearch is required to fully understand the potential effectof exercise over time and to determine essential attributesof exercise (mode, intensity, frequency, duration, and tim-ing) by cancer type and cancer treatment [24].To our knowledge the present Perioperative Rehabilita-
tion in Operation for LUng CAncer (PROLUCA) study isthe first study to investigate the clinical effects of pre- andearly postoperative rehabilitation in NSCLC patients. InPROLUCA a randomized clinical trial, the efficacy of pre-and early postoperative rehabilitation is compared withthe effect of rehabilitation initiated six weeks after surgery(usual care) in a non-hospital setting.The aim of PROLUCA is to identify the optimal tim-
ing of exercise to improve VO2peak in postoperativeNSCLC patients. The specific aims are: (1) comparisonof combined preoperative home-based exercise withpostoperative exercise regarding VO2peak and patient-reported outcomes (PROs), (2) comparison of earlypostoperative exercise (initiated as early as two weeksafter surgery) with usual care regarding VO2peak andPROs.
Sommer et al. BMC Cancer 2014, 14:404 Page 3 of 10http://www.biomedcentral.com/1471-2407/14/404
MethodsParticipants and settingsThe study will recruit and randomize 380 patients (95patients/study arm) with histologically or cytologicallyconfirmed NSCLC, stage I-IIIa (TNM classification v. 7[45]) or strong substantiated suspicion of NSCLC, referredfor surgery. All subjects are assigned for curative lungcancer surgery at Department of Cardiothoracic Surgery,Copenhagen University Hospital (Rigshospitalet). The in-clusion and exclusion criteria are described in Table 1:Subject Eligibility Criteria in the PROLUCATrial.
ProcedureThe study is conducted in accordance with the CONSORT(Consolidated Standards of Reporting Trials) statementfor non-pharmacologic interventions and the HelsinkiDeclaration [49]. Informed consent is obtained from allparticipants prior to initiation of any study procedures.The study is approved by The Danish National Committee
Table 1 Subject eligibility criteria in the PROLUCA trial
Inclusion criteria
All subjects are assigned forcurative lung cancer surgery atDepartment of CardiothoracicSurgery RT at CopenhagenUniversity Hospital (Rigshospitalet).
Screened for eligibility criteria atBispebjerg University Hospital andGentofte Hospital.
At least 18 years old.
Performance status 0–2 (WHO)[46].
Capable of participating in thedescribed tests and intervention.
Living in the City of Copenhagenor surrounding Municipalities.
Reside within driving distance ofCopenhagen Centre for Cancerand Health and capable ofmanaging transportation asnecessitated by the clinic-basedassessments and supervisedexercise interventions.
Ability to read and understandDanish.
Approval by primary surgeon. To examine for anycontraindication in participating inphysical exercise.
Exclusion criteria
Presence of metastatic disease orsurgical inoperability.
Diagnosis of Lung Cancer notverified by histological diagnosis.
Cardiac disease [6,47]. Decompensated heart failure,severe aortic stenosis, uncontrolledarrhythmia, acute coronarysyndrome.
Contraindications to maximalexercise testing as recommendedby the American Thoracic Societyand exercise testing guidelines forcancer patients [48].
on Health Research Ethics (H-3-2012-028) and the DanishData Protection Agency (2007-58-0015).The study flow is presented in Figure 1 Study Flow
PROLUCA. Using a 4-arm, randomized design, potentialsubjects will be identified and screened for eligibility andinformed about PROLUCA by the study research coor-dinators at the involved hospitals (Bispebjerg UniversityHospital and Gentofte Hospital). After referral to intendedcurative lung cancer surgery at Copenhagen UniversityHospital (Rigshospitalet), the subjects are contacted bytelephone and provided with a review of the study. If thesubjects accept to participate, the baseline assessment isperformed at Copenhagen Centre for Cancer and Health.At baseline the following assessments are performed:(1) PROs described in Table 2 Data Assessment Schedulein the PROLUCA Trial, (2) anthropometric data, (3)6MWD, (4) muscle strength (1RM in chest- and leg-press machines), (5) pulmonary function test, and (6)cardiopulmonary exercise test (VO2peak). All baselineassessments will be completed as close to time of diag-nosis as possible and repeated the day before surgery,pre-intervention (6MWD, pulmonary function, FACT-L),post-intervention, and at follow-up six months and oneyear after surgery.
Group allocation (Randomization)Following the successful completion of baseline assess-ments, participants will be randomly allocated, on an in-dividual basis, to one of the four exercise interventiongroups:Group 1: Preoperative home-based exercise and post-
operative rehabilitation initiated as early as two weeksafter surgery.Group 2: Preoperative home-based exercise and post-
operative rehabilitation initiated six weeks after surgery.Group 3: Postoperative rehabilitation initiated as early
as two weeks after surgery.Group 4: Postoperative rehabilitation initiated six weeks
after surgery (Usual practice as control group).The random allocation sequences will be concealed
from all study personnel and performed by CopenhagenTrial Unit, Centre for Clinical Intervention Research. Apermuted block design with allocation weight of 1:1:1:1will be used to generate the treatment assignments.Randomly allocated participants will remain in the samegroup for the entire duration of the intervention, asexpressed in Figure 2 PROLUCA Study Timeline. Toensure similarity of randomized groups at baseline, pa-tient randomization will be stratified based on type ofsurgery, VATS versus thoracotomy surgery.
BlindingIt is not possible to blind the participants to their actualtreatment allocation, since participants are aware whether
Figure 1 Study Flow PROLUCA.
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they initiate preoperative exercise and whether their post-operative exercise starts two or six weeks after surgery. Allstudy personnel collecting data and doing the statisticalanalyses of the data are, however, blinded to the patient al-location, and the patients are strictly informed not to re-veal their group allocation to the test personnel.
Exercise training protocols (General considerations)Preoperative exerciseThe home-based exercise program is individually designedfor each of the participants randomized to a preoperativeintervention. The ultimate goal of the preoperative home-based exercise program is to ensure that the patientsperform cardiovascular exercise of moderate-vigorous in-tensity (~60-80% of maximum heart rate (HRmax)) for atleast 30 minutes every day until surgery. The preoperativeperiod varies in length and the intention is not to exceed14 days. The preoperative exercise is monitored by a heartrate sensor (Polar Team 2 System, with off-line transmit-ters) and an exercise diary logbook.
Postoperative rehabilitationThe postoperative intervention consists of a supervised12-week rehabilitation program containing 24 group-based exercise sessions, three individual counseling ses-sions, and three group-based lessons in health-promotingbehavior. If the participants have special needs in termsof smoking cessation, nutritional counseling or patienteducation, this is offered too.The postoperative physical exercise consists of an
individually prepared supervised strength exercise –and a group-based cardiovascular exercise twice aweek (60 minutes/session) on non-consecutive days for12 weeks, a total of 24 sessions, containing the follow-ing elements:Warm-up (five minutes) and cardiovascular exercise
(25 minutes) on ergometer bike (BODY BIKE ClassicSupreme©), individually prepared strength exercise(25 minutes) carried out using five machines (Techno-gym™), leg press, chest press, leg extension, pull tochest, pull-down (upper body). The practical aim ofstrength exercise is to complete three series of 5–12
Table 2 Data assessment schedule in the PROLUCA trial
Baselinea Flw-upb Flw-upc Flw-upd Flw-upe Flw-upf
Anthropometric data and cancer disease X X X X X
Physiological measurements
Cardiorespiratory capacity (VO2peak) X X X X X
Six- minute walk distance (6MWD) X X X X X X
One-repetition-maximum (1RM) X X X X X
Heart rate (HR), Blood pressure (BP) X X X X X
Spirometric (FEV1/FEV1%) X X X X X
Patient-reported outcome
Health-related quality of life (EORTC QLQ-C30, FACT-L) X X FACT-L X X X
Symptoms and side effects (EORTC–LC13) X X X X X
Anxiety and depression (HADS) X X X X X
Well-being (SF-36) X X X X X
Distress thermometer X X X X X
Lifestyle X X X X X
Sickness absence and work status X X X X X
Social support (MSPSS) X X X X X
Other measurements
Perioperative complications X (30 days) X (30 days)
Duration of hospitalization X (30 days) X (30 days)
Survival Histological diagnosis and TNM staging XaBaseline (0 week).bFlw-up (Follow-up): Preoperation (the day before surgery).cFlw-up (Follow-up): Pre-intervention (2/6 weeks after surgery).dFlw-up (Follow-up): Post-intervention (14/18 weeks after surgery).eFlw-up (Follow-up): Six months after surgery.fFlw-up (Follow-up): One year after surgery.
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sets. Trained physiotherapists and cancer nurse spe-cialists supervise the training program following therecommended principles [50]. All exercise sessions willinclude supervised breathing exercises combined withstretching and relaxation techniques (five minutes). Allthe cardiorespiratory exercise is designed such thatparticipants begin exercising at a low intensity (~50%-60% of individually determined HRmax) which is sub-sequently increased to more moderate to vigorousintensity (~70%-80% of individually determined HRmax).
Figure 2 PROLUCA Study Timeline (three intervention groups and on
The ultimate goal for the postoperative exercise is twogroup-based exercise sessions per week, with a cardio-respiratory intensity for the first four weeks at ~50-60%of individual HRmax. The next eight weeks the intensityincreases to moderate-high intensity at ~70-90% ofindividually determined HRmax. The heart rate will bemonitored continuously throughout the cardiorespiratoryexercise using heart rate monitors and software (PolarTeam2 Pro©). All interventions will be individually tai-lored to each participant and following the principles of
e control group).
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aerobic or resistance training prescription guidelines foradults as recommended by the American College ofSports Medicine (ACSM) [50]. The ultimate goal for thestrength exercise program is to exercise with an inten-sity of ~60-80% of 1 RM two times a week for 12 weeks.To ensure progression every second week, the load isprogressively increased and the number of repetitionsare reduced starting out at 12 repetitions in three setsprogressing to 10 repetitions in three sets to a final ofeight repetitions in three sets. The progression is docu-mented in a study exercise log file for registration of theintensity of all sessions along with data on blood pres-sure prior to exercise.
Adherence ConsiderationsTo maximize adherence, several strategies will beemployed including telephone-based follow-ups. Thepatients are provided free parking in front of the centerand transport expenses are covered. The high degree ofscheduling flexibility allows participants to perform testat a convenient time and work around other competingdemands such as medical appointments, work, and familycommitments.
Study endpoints and assessmentsPrimary endpointVO2peak is evaluated by an incremental test using anelectromagnetically braked cycle ergometer (Lode CorivalErgometer©). Inspired and expired gases are analyzedbreath-by-breath by a metabolic cart (JAEGER Master-Screen CPX©). Subjects begin pedaling at seven watts andresistance increases after a predefined 10 watts rampprotocol until exhaustion or a symptom-limited VO2peakis achieved (pain, dizziness, anxiety etc.). This regimenhas previously been demonstrated to be appropriate formeasuring VO2peak in prior studies in patients withankylosing spondylitis [51]. Other similar VO2peak pro-tocols are found appropriate for measuring VO2peak inNSCLC [38,39,52].
Secondary endpointsPatient-reported outcomes (PROs) PROs will includeHRQoL, symptoms and side effects, anxiety and depres-sion, well-being, distress, lifestyle, sickness absence, workstatus, and social support. HRQoL is assessed using theintegrated system of the European Organization for Re-search and Treatment in Cancer (EORTC) for assessingthe HRQoL of cancer patients participating in inter-national clinical trials and devised through collaborativeresearch. The EORTC QLQ-C30 assesses patient symp-toms and HRQoL in lung cancer patients [53]. Symptomsand side effects will be assessed using the EORTC–LC13,which is an additional page to the EORTC-QLQ specific-ally designed to cover a wide range of lung cancer patients
varying in disease stage and treatment modality [54].EORTC measures single items and the scales range inscore from 0 to 100. A high scale score represents ahigher response level. A high score for a functional scalerepresents a high/healthy level of functioning and a highscore for the global health status/quality of life repre-sents a high HRQoL. However, a high score for a symp-tom scale/item represents a high level of symptomatologyor problems [53,54].HRQoL will also be assessed using the Functional As-
sessment of Cancer Therapy - Lung (FACT-L) scale thatcontains four subscales for physical (7-items), functional(7-items), emotional (6-items), social/family well-being(7-items) plus a lung cancer specific subscale (15-items)which will be summed to obtain the FACT-L score (all42 items) [55].General well-being is assessed using the 36-Item Short
Form Health Survey (SF-36), standard recall (four weeks).The SF-36 includes eight scales measuring general healthwith two summary scales; physical and mental componentscales [56,57]. To assess psychological well-being, theHospital Anxiety and Depression Scale (HADS) with 14items will be administered, designed to measure generalanxiety and depression for use in investigations of pa-tients with physical illness [58]. The distress thermom-eter is a validated measure of distress and consists of asingle item, with responses ranging from 0 to 10 [59].The Multidimensional Scale of Perceived Social sup-
port (MSPSS) is a 12-item scale assessing social support.Each item is answered on a seven-point Likert scale,from one: Very strongly disagree, to seven: Very stronglyagree. The scale yields three subscale scores, for Family,Friends, and Significant Others, and a Total score, whichis confirmed in a confirmatory factor analysis [60]. Inother different cancer studies, all the above-mentionedvalidated instruments were found appropriate and easyto administer [35,52,59,61].
Physiological measurementsPhysiological measurements will include: (1) functionalcapacity, (2) pulmonary function, (3) cardiovascular O2
delivery, and (4) muscle strength. (1) functional capacitywill be measured by a six-minute walking distance(6MWD) test carried out over a pre-measured distanceof 22 m and in accordance with the American ThoracicSociety (ATS) statement [62]. The 6MWD test has dem-onstrated good reliability and validity in patients withchronic obstructive lung disease [63], a patient group withsimilar symptomatology and pathophysiology. (2) Pulmon-ary Function will be determined by assessing the ForcedExpiratory Volume in one second (FEV1), and the FEV1%which is the ratio of FEV1 to the Forced Vital Capacity(FVC) using a Triple V digital volume sensor© connectedto JAEGER MasterScreen CPX©. All pulmonary function
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tests will be performed in a standing position and accord-ing to the ATS guidelines [48]. (3) Arterial O2 Saturationwill be assessed at rest and continuously during exerciseusing pulse oximetry (Nellcor, OxiMax N-65©), whichprovides the most accurate non-invasive assessment ofblood arterial O2 saturation levels. Muscle strength ismeasured by 1RM [64] using machines (Technogym™)that includes leg press (lower extremity) and chest press(pectoral muscles).
Disease-related outcomesIn all patients lung cancer subtype, stage and extent ofsurgery will be related to the effect of exercise and re-habilitation interventions.
Tracking and monitoring of adverse eventsTracking and monitoring of adverse events are assessed asfollows: (1) before every intervention- and test-session, allpatients will receive face-to-face supervision by a special-ized trained cancer nurse discussing any potential negativeside effects of the intervention assignment. All injuriesand adverse events (e.g., knee pain, back pain) will be re-corded as unintended events. In addition, heart rate andblood pressure are recorded prior to every interventionsession and repeated if any adverse events should occurduring exercise.
Statistical considerationsSample size calculationThis randomized phase II trial will accrue 380 subjectswith operable NSCLC over an accrual period of ~2 years.The present design consists of four intervention groupsof equal size, and it is assumed that no interaction occursbetween the groups. With the smallest clinical relevantdifference set at 2 mLO2
. kg-1 . min−1,95 participants arerequired in each group (power: 80%), giving a total inclu-sion of 380 patients.For each of the primary and secondary endpoints, three
separate t-tests will be used to compare each experimentalarm to the control arm in mean change across time of theendpoint. For each endpoint, the overall alpha level will becontrolled at a two-sided 0.05 by using Holm's procedure[65]. That is, Holm's procedure first ranks the three p-values from lowest to highest. The first (lowest) p-valuehas to be less than 0.05/3 (0.0167) to be significant andpermit continuation to the other t-tests. The Holm'sprocedure continues sequentially in this fashion usingalpha levels of 0.05/2 (0.025) and 0.05/1 (0.05) for theremaining two t-tests, respectively. Power for this studyis defined as the probability that at least one of the threet-tests of the arm effect on VO2peak is significant; inother words, power is the probability that the first ofthe 3 ordered t-tests are significant. We assume thatchange in VO2peak will have a standard deviation of
4.0 mL . kg-1 . min−1 as observed in previous research[27,36]. Statistical power depends upon the configur-ation of mean change in VO2peak across the 4 arms.Thus, for example, 80% power is obtained when themean change in VO2peak across Arms 1, 2, 3, and 4 is0.60, 0.60, 2.10, and 0.0 (mL . kg-1 . min−1), respectively.
Analytic planThe intention-to-treat analysis includes all randomizedparticipants in their randomly assigned allocations. Theintervention group assignment will not be altered basedon the participant's adherence to the randomly allocatedstudy arm. Patients who are lost-to-follow-up are includedin the analysis (intention to treat). For the primary ana-lysis, a multiple regression model will be used to assess achange in VO2peak on study group, the baseline value ofthe endpoint, and other pertinent baseline variables thatmay influence change in the study endpoints (e.g., co-morbid conditions/medications, self-reported exercise his-tory, age). Data from PROs will be presented as mean,standard deviation (SD), median and inter-quartile range(IQR) and all change scores (value at follow-up minusvalue at baseline) will be presented with a 95% confidenceinterval.
DiscussionThe aim of PROLUCA is to contribute with importantknowledge about the efficacy of pre- and early postop-erative rehabilitation in patients with NSCLC in a non-hospital setting.The decision to target newly diagnosed patients with
NSCLC was primarily based on the fact that these pa-tients are not often examined in relation to the effect ofrehabilitation, although they generally have a good per-formance status and prognosis after surgery and adju-vant chemotherapy. In consequence, the issue of NSCLCsurvivorship is becoming an increasingly important aspectof the multidisciplinary care of this patient group and thedemands for knowledge correspondingly important.The need for rehabilitation becomes obvious by the
fact that NSCLC patients are subject to a marked decreasein cardiorespiratory capacity due to a combination of ageand comorbidity and reinforced by the use of adjuvantcancer treatment [6]. It is well known that good pre-operative cardiorespiratory capacity leads to better post-operative conditions resulting in less postoperativecomplications in patients with NSCLC [1,5]. Furtherstudies are also warranted on other physical effects ofexercise and how to commit this group of cancer pa-tients to a more active lifestyle.Studies focusing on the effects of exercise interventions
pre- and postoperatively are required to fully understandthe potential effect of exercise over time. The optimal
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characteristics of exercise (mode, intensity, frequency, dur-ation, and timing) have yet to be determined [24].No published research in cancer rehabilitation has in-
vestigated the best timing of rehabilitation in patientswith NSCLC in a randomized clinical trial. Qualitativestudies have pointed out that cancer patients may ex-perience transition points during time of illness to whichthey are particularly vulnerable: (1) diagnosis, (2) oper-ation and hospitalization, (3) transition from hospital todaily life, and (4) return to daily life [66-72]. The timingof rehabilitation has also been indicated to of import-ance when it comes to motivation toward a healthier lifestyle in patients with a variety of cancer diagnoses [73].The ‘teachable moment’ is a term used in e.g. researchin breast cancer patients describing the transition thattakes place when the patients are diagnosed. This transi-tion can modify barriers and motivate the patient; thustiming of rehabilitation is of great importance for theoutcome [74].The PROLUCA study aims at revealing the impact
of timing of rehabilitation on VO2peak and health-promoting behavior in patients with NSCLC. The effectsix months and one year after surgery is measured.VO2peak is chosen as the primary endpoint as this testprovides the gold standard (direct) assessment of cardiore-spiratory capacity [13]. In a hospital setting it would havebeen interesting to test cardiorespiratory capacity as earlyas two weeks postoperatively, but as the intervention inPROLUCA is carried out in a non-hospital setting, thisis not possible due to safety reasons. According to theDanish Health Act from 2007 the responsibility for re-habilitation of all patients with a decrease in functionalcapacity lies with the municipalities unless medical as-sistance is needed. The same is true of patient-targetedprevention.The patients perform a VO2peak test preoperatively
and again after the intervention. The first test acts as asurrogate parameter for the starting point, and PROLUCAis therefore not capable of clarifying what happens toVO2peak shortly after surgery. Research indicates thatVO2peak spontaneously recovers to a limited degree at ap-proximately 3 months after surgery and stabilizes at ap-proximately 6 months after pulmonary resection. Anotherstudy finds a 13% decrease in VO2peak ~6 months aftersurgery [75]. As this study compares the preoperativeVO2peak with postoperative VO2peak value 6 monthsafter surgery, the best estimate possible is chosen.To obtain a patient population as close to normal daily
practice as possible where patients are suffering from avariety of comorbidity, PROLUCA limits the amount ofexclusion criteria. This makes PROLUCA unique com-pared to other studies whose selection of patients is dis-tinct. Therefore the results of PROLUCA may contributeimportantly to daily clinical practice.
With the increasing interest in the field of exercise-oncology research, more studies are now focusing on theapplication of exercise as a concomitant interventionalongside anti-cancer therapies.
SummaryEven though rehabilitation, with focus on exercise, iswidely recommended to cancer patients, informationconcerning timing and dose of exercise rehabilitation islacking when it comes to patients operated for NSCLC.To our knowledge no previous studies have been pub-lished in which postoperative rehabilitation is initiatedas early as two weeks after surgery for NSCLC. Further-more, there is a distinct need for trials including NSCLCpatients, since this group of patients is especially vulner-able due to a high burden of comorbidity, risk of relapseof the cancer disease and consequences of both surgicaland oncological treatment. In addition, the patient popula-tion included in PROLUCA is as close to those seen innormal daily practice as possible. This makes PROLUCAunique compared to other studies whose selection of pa-tients is distinct, and the results of the PROLUCA studymay contribute importantly to daily clinical practice.
AbbreviationsVO2peak: Maximal oxygen uptake; NSCLC: Non-small cell lung carcinoma;HRmax: Heart rate max; 6 MWD: Six-minute walk distance; 1 RM: One-repetition-maximum; PROs: Patient-reported outcomes; HRQoL: Healthrelated quality of life; SCLC: Small-cell lung carcinoma; VATS: Video-assistedthoracoscopic surgery; TNM: Tumor node metastasis; ACSM: AmericanCollege of Sports Medicine; EORTC: The European Organization for Researchand Treatment in Cancer; FACT-L: Functional assessment of cancer therapy –lung; SF-36: 36-item short form health survey; HADS: Hospital anxiety anddepression scale; ATS: American Thoracic Society; FEV1: Forced expiratoryvolume in one second; FVC: Forced vital capacity; FEV1%: Which is the ratioof FEV1 to the FVC.
Competing interestsThe authors declare that they have no competing interests.
Authors’ contributionsMSS: conception and design, drafting of manuscript and final approval forpublication. KT: conception and design, drafting of manuscript and finalapproval for publication. JVP: conception and design, drafting of manuscriptand final approval for publication. MM: conception and design and finalapproval for publication. MC: conception and design and final approval forpublication. KRL: conception and design and final approval for publication.SWL: conception and design and final approval for publication. CH:conception and design and final approval for publication. PC: conceptionand design and final approval for publication. JHP: conception and designand final approval for publication. HL: conception and design and finalapproval for publication. All authors read and approved the final manuscript.
AcknowledgementsThe study is supported by grants from The Center for IntegratedRehabilitation of Cancer patients (CIRE), a center established and supportedby The Danish Cancer Society and The Novo Nordisk Foundation, and thestudy is supported by the Copenhagen University Hospital, the Faculty ofHealth Sciences, University of Copenhagen, and is secured by funding fromThe Municipality of Copenhagen. The authors thank Karl Bang Christensen,Associate professor, Department of Biostatics, University of Copenhagen, forhis valuable assistance concerning biostatistics.
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Author details1Copenhagen Centre for Cancer and Health, Municipality of Copenhagen,Nørre Allé 45, DK-2200 Copenhagen, Denmark. 2Department ofCardiothoracic Surgery RT, Copenhagen University Hospital (Rigshospitalet),Blegdamsvej 9, DK- 2100, Copenhagen, Denmark. 3Pulmonary Department L,Bispebjerg Hospital, University of Copenhagen, Bispebjerg Bakke 23, DK-2400Copenhagen, Denmark. 4Department of Oncology, Copenhagen UniversityHospital (Rigshospitalet), Blegdamsvej 9, DK - 2100 Copenhagen, Denmark.5Department of Public Health, Section of Social Medicine, CopenhagenUniversity, Øster Farimagsgade 5, postbox 2099, DK-1014 Copenhagen,Denmark. 6Department of Pulmonary Medicine, Copenhagen UniversityHospital Gentofte, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark.7CopenRehab, Section of Social Medicine, Department of Public Health andCentre for Healthy Ageing, Faculty of Heath Sciences, University ofCopenhagen, Copenhagen, Denmark.
Received: 10 July 2013 Accepted: 13 May 2014Published: 4 June 2014
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doi:10.1186/1471-2407-14-404Cite this article as: Sommer et al.: Perioperative rehabilitation inoperation for lung cancer (PROLUCA) – rationale and design. BMCCancer 2014 14:404.
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Original Article
Introduction
Among the most common cancers, lung cancer has the highest mortality rate of cancer worldwide.1 Most cases are non–small cell lung cancer (NSCLC). Accurate staging of NSCLC is cru-cial for allocation to surgical treatment, which may be curative in cases of localized disease (stages I and II) and for selected patients with locally advanced disease (stage IIIA).2 The rec-ommended treatment of disseminated NSCLC and small cell lung cancer involves chemotherapy and radiation therapy.2
The number of long-term survivors after treatment of NSCLC is increasing.3 Surgical resection is still associated with potentially significant morbidity, functional limitations, and decreased quality of life. Therefore, evidence-based
rehabilitation may be an important tool to improve outcome and quality of life in this group of patients.4,5
Systematic reviews suggest that pre- and postsurgical exercise in patients with NSCLC, compared with usual
635741 ICTXXX10.1177/1534735416635741Integrative Cancer TherapiesSommer et alresearch-article2016
1Copenhagen Centre for Cancer and Health, City of Copenhagen, Copenhagen, Denmark2University of Copenhagen, Copenhagen, Denmark3Bispebjerg University Hospital, Copenhagen, Denmark4Gentofte University Hospital, Hellerup, Denmark
Corresponding Author:Maja S. Sommer, Copenhagen Centre for Cancer and Health, City of Copenhagen, Nørre Allé 45, DK-2200 Copenhagen, Denmark. Email: [email protected]
Perioperative Rehabilitation in Operable Lung Cancer Patients (PROLUCA): A Feasibility Study
Maja S. Sommer, MHS,PT1, Karen Trier, RN, MR1, Jette Vibe-Petersen, MD1, Malene Missel, RN, MScN2, Merete Christensen, MD2, Klaus R. Larsen, MD, PhD3, Seppo W. Langer, MD, PhD2, Carsten Hendriksen, MD2, Paul Frost Clementsen, MD2,4, Jesper H. Pedersen, MD, DMSc2, and Henning Langberg, PhD, DMSc2
AbstractIntroduction. Surgical resection in patients with non–small cell lung cancer (NSCLC) may be associated with significant morbidity, functional limitations, and decreased quality of life. Objectives. The safety and feasibility of a preoperative and early postoperative rehabilitation program in patients operated for NSCLC was determined in a nonhospital setting, with focus on high-intensity interval exercise. Methods. Forty patients with biopsy-proven NSCLC stages I to IIIa referred for surgical resection at the Department of Cardiothoracic Surgery RT, Rigshospitalet, University of Copenhagen, were randomly assigned to 1 of 4 groups (3 intervention groups and 1 control group). The preoperative intervention consisted of a home-based exercise program, while the postoperative exercise program comprised a supervised group exercise program involving resistance and high-intensity interval cardiorespiratory exercise 2 hours weekly for 12 weeks combined with individual counseling. The study endpoints were inclusion rate, adherence, and number of adverse events. Results. Forty patients (of 124 screened; 32%) were included and randomized into the 4 groups. The postoperative exercise was completed by 73% of the patients randomized to this intervention. No adverse events were observed, indicating that the early postoperative exercise program is safe. The preoperative home-based exercise program was not feasible due to interfering diagnostic procedures and fast-track surgery that left only 1 to 2 weeks between diagnosis and surgery. Conclusion. The early postoperative exercise program for patients with NSCLC was safe and feasible, but in a fast-track set up, a preoperative home-based exercise program was not feasible for this population.
Keywordslung cancer, exercise, rehabilitation, NSCLC, perioperative intervention
Submitted Date: 8 September 2015; Revised Date: January 13 2016; Acceptance Date: 21 January 2016
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2 Integrative Cancer Therapies
care, is associated with improved cardiopulmonary exercise capacity, increased muscle strength, as well as reduced fatigue, postoperative complications, and length of hospital stay.6-8 These reviews emphasize that an optimal exercise program is still to be determined and that prospective research in this area is needed.6-8
Preoperative exercise offered to NSCLC patients attracts attention because it may improve longevity and decrease risk of postoperative complications, but research in this field differs in design, type of intervention, and dose of exercise. The research is primarily based on case studies and studies with few and heterogeneous patients.9-11 In addition, recent research highlights the need for psychoso-cial support during the period from diagnosis to surgery.12
Evidence shows that postoperative exercise for NSCLC patients is both safe and associated with improvement of cardiorespiratory capacity and self-reported outcomes such as health-related quality of life and fatigue.13 Still more research is required to understand the potential effect of exercise on NSCLC patients and to determine how individ-ual components such as mode, intensity, frequency, dura-tion, and timing may contribute.7
Barriers for participating in rehabilitation and maintain-ing lifestyle changes are, for example, high symptom bur-den, such as side effects to the adjuvant treatment, and high prevalence of comorbidity, especially chronic obstructive pulmonary disease.14 The timing of rehabilitation is impor-tant when it comes to motivating patients to perform and sustain lifestyle changes.15 The teachable moment is a term used to describe a health event that motivates individuals to positive health behavior change. The time of diagnosis is a health event that can modify barriers and motivate patients to adopt to a healthier lifestyle.15
Silver et al defined cancer rehabilitation as
medical care that should be integrated throughout the oncology care continuum and delivered by trained rehabilitation professionals who have it within their scope of practice to diagnose and treat patients’ physical, psychological and cognitive impairments in an effort to maintain or restore function, reduce symptom burden, maximize independence and improve quality of life in this medically complex population.16(p3636)
Thus, the focus of this article is the evaluation of the exer-cise part in a rehabilitation program to patients with opera-ble lung cancer.
The advantages of performing exercise during adjuvant treatment are better physical and mental status and a reduc-tion of side effects to the adjuvant chemotherapy. These advantages are found in a variety of cancer patients.17-19
To our knowledge, no published research has studied whether initiating high-intensity interval exercise is safe in a nonhospital setting as early as 2 weeks after an operation for NSCLC. Our assumption is that introducing exercise
before initiation of adjuvant chemotherapy, thereby laying the groundwork for better adherence to the exercise pro-gram, is advantageous compared to an exercise program initiated during adjuvant chemotherapy. We assume that NSCLC patients are willing and able to participate in home-based exercise prior to surgery and also hypothesize that patients attending preoperative home-based exercise are more prepared to participate in high-intensity interval exer-cise after surgery.
Aim of the Study
The overall aim of this feasibility study was to investigate the safety and feasibility of preoperative and early postop-erative rehabilitation in a nonhospital setting, with focus on exercise, in patients undergoing surgery for lung cancer.
Methods
Patients and Settings
The PROLUCA feasibility study included 40 patients (age ≥18 years) with biopsy-proven NSCLC, stages I to IIIa20 assigned for curative surgery at the Department of Cardiothoracic Surgery, Rigshospitalet, University of Copenhagen. The inclusion criteria were the following: assigned for curative lung cancer surgery, at least 18 years old, performance status 0 to 2 (World Health Organization),21 resident of the City of Copenhagen or a surrounding munic-ipality, able to read and understand Danish, and approval by primary surgeon. The exclusion criteria were the following: the presence of metastatic disease or surgical inoperability, diagnosis of lung cancer not verified by biopsy, severe car-diac disease, and contraindications to maximal exercise testing as recommended by the American Thoracic Society and by exercise testing guidelines for cancer patients.22
Procedure
The study was conducted in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement for nonpharmacologic interventions and the World Medical Association Declaration of Helsinki.23,24 Written informed consent was obtained from all patients prior to initiation of any study procedures. The study was approved by the Danish National Committee on Health Research Ethics (File No. H-3-2012-028) and the Danish Data Protection Agency (File No. 2007-58-0015).
The study design is presented in Figure 1. Using a 4-arm, randomized design, potential subjects were identified and screened for eligibility and contacted by the study research coordinators at the referral departments at Bispebjerg and Gentofte Hospitals. After referral to surgery, the subjects were contacted by telephone and informed of the purpose and design of the study. Next, written informed consent was
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Sommer et al 3
obtained and baseline assessment was performed at the Copenhagen Centre for Cancer and Health. At baseline the following assessments were performed (Table 1): (1) anthropometric data and tumor node metastasis (TNM) stage, (2) cardiorespiratory capacity expressed as maximal oxygen uptake (VO
2peak) evaluated by an incremental test
using an electromagnetically braked cycle ergometer (Lode Corival Ergometer, Groningen, Netherlands) where inspired and expired gases were analyzed breath-by-breath by a met-abolic cart (JAEGER MasterScreen CPX, Care Fusion, San Diego, CA), (3) 6-minute walk distance (6MWD), (4) mus-cle strength measured by a 1 repetition maximum (1RM) in chest and leg press, (5) pulmonary function test (spirome-try), and (6) patient-reported outcomes. All baseline assess-ments were completed as close to the time of diagnosis as possible and were repeated the day before surgery, postint-ervention, and at follow-up 6 months and 1 year after sur-gery. Assessments at pre-intervention were 6MWD, pulmonary function, and Functional Assessment of Cancer Therapy–Lung (FACT-L).
Group Allocation (Randomization)
Following the successful completion of baseline assess-ments, patients were randomized and allocated, on an indi-vidual basis, to 1 of the 4 exercise intervention groups:
1. Preoperative and postoperative exercise initiated 2 weeks after surgery
2. Preoperative and postoperative exercise initiated 6 weeks after surgery
3. Postoperative exercise initiated 2 weeks after surgery
4. Current standard care, postoperative exercise initi-ated 6 weeks after surgery
The random allocation sequences were concealed from all study personnel and performed by Copenhagen Trial Unit, Centre for Clinical Intervention Research. Randomly allo-cated patients remained in the same group for the entire duration of the intervention.
The intention-to-treat analysis included all randomized participants in their randomly assigned allocations. The intervention group assignment was not altered based on the participant’s adherence to the randomly allocated study arm. Patients who were lost to follow-up were included in the analysis (intention-to-treat).
Exercise Training Protocols
Preoperative Exercise. Individually designed according to functional status and comorbidity for each patient ran-domized to the preoperative intervention, the home-based exercise program consisted of 30 minutes of cardiorespiratory exercise daily until surgery. The exer-cise period varied in length due to the time available before surgery. The preoperative exercise was monitored by a heart rate monitor and software (Polar Team2, Polar Electro Oy, Kempele, Finland) and an exercise diary logbook.
Postoperative Exercise. The postoperative exercise intervention was a part of the rehabilitation services available at a rehabili-tation center described in Figure 2. Every participant was ini-tially screened for rehabilitation needs following a professional rehabilitation guide covering the following topics: disease specific, social network, relatives, psychological, existential, diet, smoking, alcohol, physical activity, sexuality, sleep, and stress. The rehabilitation guide was based on the theoretical framework by the World Health Organization on International Classification of Functioning,25 the “self-efficacy theory” by
Figure 1. Timeline for the PROLUCA feasibility study.
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4 Integrative Cancer Therapies
Bandura,26 and motivational interviewing by Miller.27 The exercise intervention consisted of 24 group-based exercise sessions combined with 3 individual counseling sessions and 3 group-based lessons in health-promoting behavior. If the patients had special needs in terms of smoking cessation, nutritional counseling, or patient education, this was also offered as part of the rehabilitation. The postoperative exer-cise consisted of individually tailored, supervised strength exercise and group-based cardiorespiratory exercise twice a week (60 minute/session) on nonconsecutive days for 12 weeks, for a total of 24 sessions. It included the following exercises.
Warm-up (5 minutes) and cardiorespiratory exercise (25 minutes) on an ergometer bike (BODY BIKE Classic Supreme, TKO, Houston, TX), individually tailored strength exercise (25 minutes) carried out using 5 machines
(Technogym, Cesena, Italy), leg press, chest press, leg extension, pull to chest, and pull down (upper body). Trained physiotherapists and cancer nurse specialists super-vised the training program following principles recom-mended by the American College of Sports Medicine.28 All exercise sessions included supervised breathing exercises combined with stretching and tension-release techniques (5 minutes). All interventions were individually tailored to each patient and followed the principles of aerobic or resis-tance training prescription guidelines for adults as recom-mended by the American College of Sports Medicine.28 The high-intensity interval exercise consisted of a warmup period where the participants aimed at reaching a level at 85% of individually determined HRmax (5 minutes) fol-lowed by a short rest (1 minute). The duration of the high-intensity interval exercises was 25 minutes. In each interval
Table 1. Baseline Characteristics.
Variables Total (N = 40)Early Exercise (n = 18),
Groups 1 + 3Late Exercise (n = 22),
Groups 2 + 4
Age (years), median (range) 68 (36-85) 67 (36-79) 71 (56-86)Female, n (%) 24 (60%) 10 (56%) 14 (64%)Body mass index (kg/m2), mean (SD) 25 (5) 25 (5) 25 (4)Academy professional degree <3 years, n (%) 17 (43%) 6 (33%) 11 (50%)Smoking history, N = 40 (groups 1 and 3, n = 18; groups 2 and 4, n = 22) Currently smoking, n (%) 10 (25%) 7 (39%) 3 (14%) Never smoked, n (%) 2 (5%) 1 (6%) 1 (5%) Ex-smoker, n (%) 28 (70%) 10 (55%) 18 (81%) Years smoking, mean (SD) 41 (15) 44 (12) 38 (13)Presence of comorbidity (5 patients had none of the comorbidities mentioned below) Hypertension, n (%) 15 (38%) 6 (33%) 9 (41%) Dyslipidemia, n (%) 9 (23%) 4 (22%) 5 (23%) Diabetes, n (%) 6 (15%) 3 (17%) 3 (14%) Atrial fibrillation, n (%) 2 (5%) 0 2 (9%) COPD, n (%) 8 (20%) 2 (11%) 6 (27%) Rheumatic diseases, n (%) 12 (30%) 5 (28%) 7 (32%) Other type of cancer, n (%) 6 (15%) 4 (22%) 2 (9%) Depression, n (%) 4 (10%) 1 (6%) 3 (14%) Medication, number of drugs, median (range) 3 (1-6) 2 (1-5) 3 (2-6)Pulmonary function FEV
1 (L/s), mean (SD) 2.4 (0.6) 2.5 (0.5) 2.3 (0.6)
FEV1 (L/s), % predicted (SD) 94 (23.7) 95 (26.1) 93 (22.2)
FEV1/VC (%), mean (SD) 67.4 (8.7) 68 (6) 68 (10)
Cardiorespiratory capacity Fitness (mL/kg/min), mean (SD) 19.4 (5) 21.5 (6) 17.6 (4) Peak oxygen uptake (L/min), mean (SD) 1.40 (0.39) 1.53 (0.33)* 1.28(0.40)* 6MWD, mean (SD) 477 (81) 497 (92) 461 (70)TNM stage Stage I (a + b), n (%) 11 (27%) 5 (28%) 6 (27%) Stage II (a + b), n (%) 24 (60%) 12 (67%) 12 (55%) Stage IIIa, n (%) 5 (13%) 1 (5%) 4 (18%)
Abbreviations: n, number; SD, standard deviation; COPD, chronic obstructive lung disease; FEV1, forced expiratory volume in 1 second; VC,
vital capacity; 6MWD, 6-minute walk distance.*P > .05.
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(1-2 minutes), the participants aimed at reaching a level of 85% to 100% of individually determined HRmax in each interval followed by a short rest (1 minute). The high-inten-sity interval exercise was followed by a cool down period (2 minutes).
The ultimate goal for the postoperative exercise was 2 group-based exercise sessions per week, with a cardiorespira-tory intensity for the first 4 weeks of approximately 50% to 60% of individual HRmax. In the next 8 weeks, the intensity was increased to moderate-high intensity at approximately 70% to 90% of individually determined HRmax. The ultimate goal of the strength exercise program was to exercise with an intensity of approximately 60% to 80% of 1RM 2 times a week for 12 weeks. To ensure progression, every other week the load was progressively increased and the number of repe-titions reduced, starting out at 12 repetitions in 3 sets, pro-gressing to 10 repetitions in 3 sets, to a final of 8 repetitions in 3 sets. The protocol study by Sommer et al describes the pre- and postoperative interventions in further detail.29
Adherence Considerations
To maximize adherence, several strategies were employed: telephone-based follow-up, free parking in front of the
center, and remuneration for transport expenses. A high degree of scheduling flexibility allowed patients to perform tests at a convenient time to allow space for competing demands such as medical appointments, work, and family commitments.
Study Endpoint and Assessment
Tracking and Monitoring of Adverse Events. Tracking and monitoring of adverse events took place as follows: before every intervention and test session, all patients received face-to-face supervision by a specialist cancer nurse to dis-cuss any potential negative side effects of the intervention tasks. All injuries and adverse events (eg, knee pain, back pain) were recorded as unintended events. In addition, heart rate and blood pressure were recorded prior to every inter-vention session and repeated if any adverse events occurred during exercise.
Adherence to the Program. Reasons for not attending the program were assessed immediately after the participants decided not to participate or decided to drop out of the pro-gram. The assessment was performed by specially trained cancer staff and conducted either by phone or face-to-face.
Figure 2. Rehabilitation services available between diagnosis and follow-up at the rehabilitation center.
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6 Integrative Cancer Therapies
Adherence to exercise sessions was monitored by trained staff, and reasons for not attending a session were assessed immediately after absence from exercise.
Statistical Analysis
Descriptive statistics and paired t tests were calculated using SAS/STAT software. Statistical significance was set at P < .05. Baseline values of the study populations were compared with values measured at postintervention and 1-year follow-up. The values are expressed as mean ± stan-dard deviation (SD). Pared t tests were also performed to reveal tendencies in patients who exercised for more or less than 70% of the exercise sessions. Cardiac rehabilitation normally sets the cutoff for adherence to both the number of training sessions prescribed and the duration of the pre-scribed program as at least 80%.30 In cancer rehabilitation, there is no standard practice on how to set adherence to an exercise intervention. Based on the small number of partici-pants in this study, we chose a cutoff value for adherence as at least 70% of the exercise sessions.
Results
Study Population and Characteristics
A total of 180 patients were screened for eligibility, 124 of whom were eligible. Forty patients (32%) were included and randomized. Table 1 presents the baseline characteristics of the 40 patients included and of the pooled subgroups with either early (groups 1 + 3) or late (groups 2 + 4) exercise intervention. The 2 most frequent reasons given by patients for not attending the study were either logistical ones or that the patients had too much to think about prior to surgery (Figure 3). The 40 patients included in the study had a mean age of 68 years, and the majority were retired (Table 1). The most frequent comorbidities (registered from the medical records) were hypertension, dyslipidemia, rheumatic disease, and chronic obstructive pulmonary disease. Five patients had no comorbidity, and 16 patients were categorized as having multiple morbidities. At baseline, 70% were ex-smokers, and 25% currently smoked. The baseline cardiopulmonary capac-ity of the included patients was 19.4 mL/kg/min and a forced expiratory volume in 1 second (FEV
1 at 2.4 L/s and a FEV
1/
vital capacity [VC] at 67.4%; Table 1).The VO
2peak and fitness measured at baseline was sig-
nificant higher in the early exercise group compared to the late exercise group (Table 1).
Nine patients (22%) underwent open thoracotomy sur-gery, of which 3 participated in early exercise group and 6 participated in late exercise group. Thirty-one (78%) patients received video-assisted thoracic surgery and 13 (33%) received adjuvant chemotherapy (9 in early exercise groups and 4 in late exercise groups).
The types of operation that were performed were primar-ily lobectomy (83%); only 1 pneumonectomy was per-formed (2%). The patient that had a pneumonectomy was randomized to the early intervention group and had an adherence to the exercise program of 80%. Other types of operations performed were bilobectomy (5%), wedge resec-tion (8%), and video-assisted thoracic surgery segmental resection (2%).
Safety and Adherence to the Perioperative Exercise
Safety. There were no adverse events reported or observed, and no patients showed spontaneous or unexpected reac-tions to initiating exercise 2 weeks after surgery.
Adherence to Home-Based Preoperative Exercise. Twelve out of 18 patients randomized to preoperative exercise were instructed in the home-based exercise program. The combi-nation of medical procedures and lack of time prior to oper-ation meant 6 patients did not receive instruction, and 1 patient who had received instruction failed to start due to lack of motivation. The average number of days possible for exercise before surgery was 8 days, with a range between 2 and 15 days. It was only possible for 3 out of the 12 patients to accomplish exercises daily prior to surgery (Table 2).
Adherence to Supervised Group Exercise After Surgery. The supervised group exercise after surgery was completed by 73% of the patients. Postoperative exercise adherence to 24 group-based sessions was ≥70% in 15 patients out of 29 (Table 2). Four out of the 29 never exercised, but as the study is designed as an intention-to-treat study, results from all 29 are provided according to the objectives of the study. For further in-depth analysis of the potential efficacy of exercise, analysis of the 25 completers was also carried out. The results did not change the significance of the results presented in Table 5, which is why results for the completers alone are not presented.
The primary reasons for cancelling exercise sessions were hospitalization/appointments at the hospital, lack of motivation, or lack of time. There was no difference in adherence between the groups that initiated exercise 2 weeks after surgery (groups 1 and 3) compared to those who started exercise 6 weeks after surgery (groups 2 and 4; Table 2). Patients who performed preoperative exercise were evenly distributed between patients who did at least 70% of the sessions or who did less than 70% of them.
In the early intervention group (groups 1 and 3), the average onset of exercise was 18 days postsurgery, with a range of 13 to 29 days, and in the late intervention group the average onset of exercise was 47 days, with a range of 22 to 80 days. One patient, in the early intervention group, started exercise 49 days after surgery, which was around the time
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Sommer et al 7
the late intervention (groups 2 and 4) was initiated. As a result, this patient could no longer be categorized in the early initiation of exercise group.
The distribution of patients who performed preoperative exercise was even evenly distributed between patients who exercised for at least 70% or for less than 70% of the post-operative sessions. The mean intensity of the strength exer-cise was for the chest press 67% (SD 20) of 1RM and for leg press 69% (SD 22) of 1RM during the 24 exercise ses-sions. The intensity of the cardiorespiratory exercise for the first 4 weeks was at 74% (SD 8) of individual determined maximum heart rate and for the last 8 weeks at 77% (SD 4) of individual determined maximum heart rate.
Dropouts. Eleven patients dropped out during the interven-tion, primarily due to either lack of motivation to complete or side effects to the adjuvant chemotherapy. Patients receiving adjuvant chemotherapy were evenly distributed between completers and dropouts (Table 3). The prevalence of patients receiving adjuvant chemotherapy was lower in patients who exercised for 70% to 100% of the 24 exercise sessions com-pared to patients who exercised 0% to 69% (Table 3). There was no difference between completers and dropouts regard-ing demographic data, stage of disease, or type of surgery.
Dropouts were evenly distributed between the groups who initiated exercise 2 and 6 weeks after surgery (Table 2).
Postoperative Complications, Recurrence, and Mortality
Out of all of the registered pulmonary and cardiac complica-tions, only one occurred during the exercise intervention and it involved pulmonary pneumatocele and was not evaluated as an adverse event caused by the exercise. All other pulmo-nary and cardiac complications occurred before the patients initiated the exercise intervention. The overall prevalence of pulmonary postoperative complications within 30 days after surgery was 23% and was highest in the early exercise group (groups 1 and 3; Table 4). The prevalence of cardiac compli-cations was 13%, and the distribution of cardiac complica-tions was evenly distributed between early and late exercise. Two patients experienced recurrence and 3 patients died within the first year after surgery (Table 4).
Changes in Physiological Capacity
Table 5 shows the results of physiological capacity change scores from baseline to postintervention and from baseline
Figure 3. Flow PROLUCA feasibility study.
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8 Integrative Cancer Therapies
to 1-year follow-up (VO2peak, fitness, 6MWD, 1RM,
FEV1, and FEV
1/VC).
There was a significant increase postintervention in walking distance (P = .0229) for patients who participated in at least 70% of the sessions. This effect on walking dis-tance was not reproduced at the 1-year follow-up. There was a significant improvement in strength for patients who participated in at least 70% of the sessions. This improve-ment was found for leg press in both the postintervention and at the 1-year follow-up (P = .0220 and P = .0443). Correspondingly, the improvement for chest press was also significant (P = .0029 and P = .0129).
Independent of adherence to exercise, there was a trend in mean decrease in fitness of 1.9 mL/kg/min from baseline
to postintervention (P = .0741). This trend was retained at the 1-year follow-up (P = .0637).
Discussion
This feasibility study showed that rehabilitation with high-intensity interval exercise initiated 2 weeks after surgery in NSCLC patients in a nonhospital setting was safe and fea-sible. The preoperative home-based exercise was inconsis-tent and not feasible in the present setup due to the short time interval between referral and surgery (fast-track surgi-cal program).
Preoperative Home-Based Exercise
To our knowledge only one study has investigated the effect of a home-based exercise training program prior to surgery in patients who are potentially candidates for lung resec-tion, but the patients were younger and diagnosed with early-stage lung cancer compared to the patients in the pres-ent study.31 Coats et al found good adherence to a 4-week home-based exercise intervention as all of the included patients (n = 16) completed more than 75% of the pre-scribed exercise sessions.31 In Denmark, the maximum waiting time for surgery after a diagnosis of lung cancer is, by law, specified not to exceed 2 weeks. Therefore, a 4-week preoperative training program would not be possible.
Table 3. Distribution of Patients Receiving Adjuvant Chemotherapy in Relation to Postoperative Exercise Adherence (24 Sessions).
Patients Included Completed Exercise Exercise ≥70% Exercise <70% Dropout
Total number, n 40 29 15 14 11Numbers receiving chemotherapy, n (%) 13 (33%) 9 (31%) 2 (13%) 7 (50%) 4 (36%)
Table 4. Postoperative Complications, Recurrence, and Mortality.
Pulmonary complications, N = 40, n (%)a 9 (23%) Early, n = 18, n (%) 6 (33%) Late, n = 22, n (%) 3 (14%)Cardiac complications, N = 40, n (%)a 5 (13%) Early, n = 18, n (%) 2 (11%) Late, n = 22, n (%) 3 (14%)Recurrenceb, N = 40, n (%) 2 (5%)Mortalityb, N = 40, n (%) 3 (8%)
aData collected 30 days after surgery.bData collected at 1-year follow-up.
Table 2. Adherence to perioperative exercise.
Preoperative exercise (home-based) (n = 18) Instruction given to, n (%) 12 (67%) Possible days for exercise, mean (range) 8 (2-15)Days of self-reported exercise out of days possible (%) (n = 12) Exercise ≥70%, n (%) 8 (67%) Exercise <70%, n (%) 4 (33%)Postoperative exercise adherence to 24 sessions (group exercise) (n = 29) Exercise ≥70%, n (%) 15 (52%) Exercise <70%, n (%) 14 (48%)Participation ≥70% in early and late postoperative interventions (n = 15) Early exercise, n (%) 7 (47%) Late exercise, n (%) 8 (53%)Dropouts in early and late postoperative interventions (n = 11) Early exercise, n (%) 5 (45%) Late exercise, n (%) 6 (55%)Initiation of exercise: early (n = 15) and late (n = 16) intervention groupsEarly, number of days after surgery, mean (range) 18 (13-29)Late, number of days after surgery, mean (range) 47 (22-80)
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Table 5. Physiological Capacity Change Scores (Evaluated in Relation to Adherence to Exercise).
Variable
Baseline (N = 40)
Postintervention (n = 29)
One Year (n = 28)
Difference Between Baseline and Postintervention
Difference Between Baseline and 1-Year Follow-up
Mean (SD) Mean (SD) Mean (SD) Mean (95% CI) P Value Mean (95% CI) P Value
VO2peak (L/min) 1.40 (0.39) 1.35 (0.54) 1.38 (0.40) −0.12 (−0.27 to 0.03) .1038 −0.09 (−0.21 to 0.02) .1125
Exercise ≥70% 1.45 (0.45) 1.45 (0.55) 1.35 (0.44) −0.08 (−0.26 to 0.11) .3809 −0.07 (−0.25 to 0.11) .4124 Exercise <70% 1.37 (0.35) 1.21 (0.48) 1.41 (0.37) −0.19 (−0.50 to 0.12) .1876 −0.12 (−0.30 to 0.06) .1714Fitness (mL/kg/min) 19.4 (4.8) 18.8 (6.4) 18.4 (2.9) −1.9 (−3.9 to 0.2) .0741 −1.8 (−3.7 to 0.11) .0637 Exercise ≥70% 19.2 (5.3) 18.1(5.7) 17.7 (3.1) −1.3 (−3.3 to 0.7) .1870 −1.3 (−4.35 to 1.7) .3676 Exercise <70% 19.6 (4.5) 19.8 (7.7) 19.2 (2.5) −2.8 (−8 to 2.4) .2393 −2.4 (−5.2 to 0.3) .07826MWD (m) 477 (81) 512 (80) 517 (92) 16 (−3 to 35) .0947 22 (−9 to 53) .1615 Exercise ≥70% 495 (63) 525 (67) 507 (113) 28 (4 to 51) .0229 20 (−30 to 69) .4093 Exercise <70% 465 (90) 486 (101) 531 (59) −7 (−43 to 29) .6659 25 (−16 to 67) .19771RM Leg (kg) 107 (39) 121 (46) 130 (58) 9 (−3 to 22) .1441 21 (5 to 37) .0136 Exercise ≥70% 112 (41) 140 (67) 133 (51) 30 (5 to 55) .0220 18 (1 to 36) .0443 Exercise <70% 104 (39) 100 (28) 118 (47) −6 (−21 to 9) .3526 10 (−12 to 33) .34311RM Chest (kg) 34 (13) 36 (13) 37 (16) 3 (0 to 6) .0499 3 (0 to 6) .0249 Exercise ≥70% 33 (12) 39 (15) 35 (14) 5 (2 to 8) .0029 4 (1 to 7) .0129 Exercise <70% 34 (15) 30 (8) 40 (18) −2 (−7 to 4) .4746 2 (−4 to 7) .4703FEV
1, L/s (SD) 2.4 (0.6) 2.2 (0.5) 2.2 (0.4) −0.2 (−0.4 to 0) .0830 −0.2 (−0.3 to 0) .0140
FEV1/VC, % (SD) 67.4 (8.7) 66.7 (10.9) 63.9 (8.4) −1.3 (−3.8 to 1.2) .2861 −6.3 (−9.5 to −3) .0006
Abbreviations: SD, standard deviation; CI, confidence interval; 6MWD, 6-minute walk distance; FEV1, forced expiratory volume in 1 second; VC, vital capacity.
Some possible advantages of home-based preoperative programs are greater flexibility and convenience for patients, low time consumption, and more manageable financially compared to preoperative interventions in an outpatient setting.32,33 In our study, 28% of eligible patients found physical activity before surgery unmanageable in the fast-track setting. In the present feasibility study, patients who performed preoperative exercise were evenly distrib-uted between patients who exercised for at least 70% or for less than 70% of the postoperative sessions, which indi-cates that preoperative home-based exercise had no influence.
Preoperative exercise is a component in the emerging medical discipline called Prehabilitation.34 Silver and Baima define prehabilitation
as a process on the cancer continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment and includes physical and psychological assessments that establish a baseline functional level, identify impairments, and provide interventions that promote physical and psychological health to reduce the incidence and/or severity of future impairments.34(p716)
The potential benefit of prehabilitation to cancer patients and the research within this area seems promising in terms of reducing morbidity, improving physical and psychological function, and decreasing hospital readmissions.34
Supervised Group Exercise After Surgery
In a nonhospital setting, the present study is the first to dem-onstrate that supervised, group-based high-intensity inter-val exercise initiated 2 weeks after surgery is safe in NSCLC patients. The present study also demonstrates that the patients could exercise with the average intensity we have prescribed. The intensity of the cardiorespiratory exercise was for the first 4 weeks at 73% of individual determined HRmax. These results indicate that the patients in the pres-ent study were able to exercise with a higher intensity than the 50% to 60% we prescribed.
Previous research concerning early postoperative exer-cise in operable lung cancer patients is based on studies with limited intensity and duration of exercise. In the major-ity of the studies, the exercise is initiated the day after oper-ation and carried out during hospitalization. These studies find that exercising shortly after an operation for NSCLC is safe, but the studies are characterized by having small sam-ple sizes.35-37 Recently published research investigated the efficacy of home-based postoperative exercise, but the interventions in these studies are characterized by low-intensity exercise interventions.38,39 The present study found a higher prevalence of pulmonary complications in the group that initiated exercise 2 weeks after surgery, but since the complications occurred before exercise was initi-ated there was no causal relation. The prevalence of pulmo-nary and cardiovascular postoperative complications in the present study is comparable to other findings in a cohort
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10 Integrative Cancer Therapies
study by Boffa et al.40 Edvardsen et al carried out a random-ized clinical trial (RCT) in NSCLC patients, where the intervention was initiated 4 to 6 weeks after surgery and carried out in a fitness center near the patients’ home. In addition to demonstrating significant improvements in both physical performance and health-related quality of life, the study found the intervention to be safe, with only one adverse event reported (a hip fracture).41 Thus, with regard to safety their study supports our results.
Missel et al interviewed patients with operable NSCLC and found that motivation for participation in an exercise program depended on patient expectations concerning the physical benefits and the comfort of having health care pro-fessionals present.12 This underlines the importance of hav-ing specialized cancer nurses and physiotherapists to manage the exercise instead of attending a public fitness center.
Seventy-three percent of patients in the present study completed the supervised group exercise and adherence to the program exceeded 70% in half of the patients. In the study by Edvardsen et al, mean adherence to the exercise intervention was 88%, but technically some participants could exceed 100%. Other studies reported an adherence of around 50% to 55%.42,43 The present study found no differ-ence between early and late intervention in terms of adher-ence or dropouts. Among the patients receiving adjuvant chemotherapy, only 2 patients (n = 13) managed to exercise for at least 70% of the sessions, indicating the difficulty of attending exercise during adjuvant chemotherapy.
In the present study, 33% of the patients received adjuvant chemotherapy, which is comparable to the NSCLC popula-tion in Denmark.3 Edvardsen et al41 found that patients receiving the last courses of chemotherapy had to postpone their training sessions until they had completed the adjuvant treatment. In contrast, Jones et al44 found good adherence in the same group of patients receiving chemotherapy, but the effect of the intervention was inferior to the findings in the study by Edvardsen et al,41 and the second most frequent rea-son for dropping out of the present study was side effects of the adjuvant treatment, reported by 27% of the total number of dropouts. The prevalence of patients receiving adjuvant chemotherapy was highest in the group with early exercise. These results show that exercising during adjuvant treatment is feasible and supported by findings in inoperable lung can-cer as well as other cancer diagnoses.17,19
The present study found a significant improvement in strength for patients who exercised for at least 70% of the sessions. This improvement was found for leg and chest press, both postintervention and at the 1-year follow-up and is comparable to the findings of the RCT by Edvardsen et al,41 where the same significant improvement in leg press was found (mean difference at 29.5 kg P > .001). This improvement is of great importance as muscle strength is inversely associated with all-cause mortality.45
Our feasibility study also found a trend toward a mean decrease in fitness of 1.9 mL/kg/min from baseline to pos-tintervention. These findings are not supported in other studies published in NSCLC patients. Since the study is underpowered, the results must be interpreted with caution.
Strength and Limitations
The strength of this study is the precise surveillance of adverse events, the reported reasons for dropping out, and the precise detection of postoperative complications. Additional strengths are the use of well-validated objective measurements, blinded professionals collecting data, and the statistical analysis.
The fact that only 32% of the eligible patients partici-pated in the present study can result in a selection bias because the present population might not be representative of the population operated on for NSCLC in Denmark. The low recruitment rate could also affect possibilities to imple-ment these results in a clinical setting. It might be that the patients choosing to participate in the present study repre-sents a group with better physical fitness than the group that did not want to participate in the study. A comparison of the patients in the present study with cohort studies in patients with NSCLC reveals similarities regarding age, sex, pulmo-nary function, and comorbidities.40,46
A methodological weakness of this study is that blinding participants to their actual treatment allocation was not pos-sible since participants were aware of whether they initiated preoperative exercise and whether their postoperative exer-cise started 2 or 6 weeks after surgery. Another limitation in the present study is the low number of participants and thereby the risk of finding or not finding statistically signifi-cant results when using a t test to analyze the mean differ-ence from baseline to postintervention and from baseline to 1 year after surgery. Therefore, the result from the present study must be interpreted with caution. It is also very impor-tant to emphasize that the t test only allows us to investigate the effect on a certain time point and we cannot conclude anything about the effect over time.
Conclusion
This study shows that patients with operable NSCLC are able to initiate high-intensity interval group exercise 2 weeks after lung resection in a nonhospital setting. Early, supervised, group-based high-intensity interval exercise is both safe and feasible. In the study setting, the preoperative home-based exercise was not feasible due to low recruit-ment rate and the short time interval between referral and surgery. Our findings are currently under investigation in an RCT study examining the effect of a postoperative exercise intervention initiated either 2 or 14 weeks after surgery. To
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Sommer et al 11
ensure a higher inclusion rate, the preoperative exercise intervention has been omitted.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, suthorship, and/or publication of this article: This study was supported by grants from the Center for Intregrated Rehabilitation of Cancer Patients (CIRE), which was established by and receives support from the Danich Cancer Society and the Novo Nordisk Foundation.
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Original Article
Introduction
Health-related quality of life (HRQoL), including physical, psychological, and social functioning, has become an important topic in clinical oncology during and after treat-ment for lung cancer.1 Furthermore, many randomized con-trolled trials include HRQoL measures as a valid and useful endpoint in addition to the traditional clinical outcomes of, for example, mortality and morbidity.2 As predictor of sur-vival, HRQoL reflects how patients with lung cancer expe-rience the impact of the cancer disease and its treatment on their quality of daily living, thus making HRQoL an impor-tant clinical outcome.3-6
Kurtz et al7 describe the connection between physical symptoms as a result of the disease combined with subse-quent treatment and decline in physical function and its
668258 ICTXXX10.1177/1534735416668258Integrative Cancer TherapiesSommer et alresearch-article2016
1Copenhagen Centre for Cancer and Health, Copenhagen, Denmark2University of Copenhagen, Copenhagen, Denmark3Rigshospitalet, University of Copenhagen, Copenhagen, Denmark4Bispebjerg University Hospital, Copenhagen, Denmark5Gentofte University Hospital, Hellerup, Denmark
Corresponding Author:Maja S. Sommer, Copenhagen Centre for Cancer and Health, City of Copenhagen, Nørre Allé 45, DK-2200 Copenhagen, Denmark. Email: [email protected]
Changes in Health-Related Quality of Life During Rehabilitation in Patients With Operable Lung Cancer: A Feasibility Study (PROLUCA)
Maja S. Sommer, MHS, PT1, Karen Trier, MR, RN1, Jette Vibe-Petersen, MD1, Karl B. Christensen, PhD2, Malene Missel, PhD, RN3, Merete Christensen, MD3, Klaus R. Larsen, MD, PhD4, Seppo W. Langer, MD, PhD3,4, Carsten Hendriksen, MD2, Paul F. Clementsen, MD3,5, Jesper H. Pedersen, MD, DMSc3, and Henning Langberg, MD, DMSc2
AbstractIntroduction: Surgical resection in patients with non–small cell lung cancer (NSCLC) may be associated with significant morbidity, functional limitations, and decreased quality of life. Objectives: The objective is to present health-related quality of life (HRQoL) changes over time before and 1 year after surgery in patients with NSCLC participating in a rehabilitation program. Methods: Forty patients with NSCLC in disease stage I to IIIa, referred for surgical resection at the Department of Cardiothoracic Surgery RT, Rigshospitalet, were included in the study. The rehabilitation program comprised supervised group exercise program, 2 hours weekly for 12 weeks, combined with individual counseling. The study endpoints were self-reported HRQoL (Functional Assessment of Cancer Therapy–Lung, European Organization for Research and Treatment in Cancer–Quality of Life Questionnaire-QLQ-C30, Short-Form-36) and self-reported distress, anxiety, depression, and social support (National Comprehensive Cancer Network Distress Thermometer, Hospital Anxiety and Depression Scale, Multidimensional Scale of Perceived Social Support), measured presurgery, postintervention, 6 months, and 1 year after surgery. Results: Forty patients were included, 73% of whom completed rehabilitation. Results on emotional well-being (P < .0001), global quality of life (P = .0032), and mental health component score (P = .0004) showed an overall statistically significant improvement during the study. Conclusion: This feasibility study demonstrated that global quality of life, mental health, and emotional well-being improved significantly during the study, from time of diagnosis until 1 year after resection, in patients with NSCLC participating in rehabilitation.
Keywordslung cancer, exercise, rehabilitation, NSCLC, HRQoL
Submitted date: 20 May 2016; Revised Date: 3 August 2016; Acceptance Date: 6 August 2016
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effect on emotional well-being. They find that the severity of cancer-related symptoms, restrictions in social function-ing, and radiation treatment were the primary predictors of depressive symptoms in elderly lung cancer patients during the first year after diagnosis. As a result, early identification of psychosocial difficulties in patients with non–small cell lung cancer (NSCLC) is recommended.7 Lowery and col-leges also hypothesize that the decline in HRQoL in post-surgical NSCLC survivors reflects a decline in the physical component more than a decline in the emotional component of HRQoL.8
Factors negatively associated with HRQoL following lung cancer surgery include the extent of resection,9 postop-erative pain,10 degree of comorbidity,10 distressed mood,11 and fatigue.12 Cerfolio and Bryant observed that pneumo-nectomy leads to worse HRQoL than lobectomy and that preoperative HRQoL is an important predictor of postoper-ative HRQoL.13
Despite a history of lung cancer, most cancer survivors appear to believe that they have good to excellent health, and although many lung cancer survivors already practice behav-iors associated with a healthy lifestyle, there are still many who do not and who may need help in selected areas.14 Engaging in physical activity among lung cancer survivors is particularly low during the early posttreatment period. Lung cancer survivors who currently meet physical activity guidelines report better quality of life in multiple domains than less active individuals, but as most lung cancer survi-vors do not meet physical activity guidelines, they may ben-efit from interventions promoting regular physical activity.1
The overall aim of this feasibility study was to investi-gate the safety and feasibility of preoperative and early postoperative rehabilitation in a nonhospital setting, with a focus on exercise, in patients undergoing surgery for lung cancer. Sommer et al15 recently reported on this topic. The aim of this article is to present HRQoL changes over time before and 1 year after surgery in the same population of patients with NSCLC participating in a rehabilitation program.
Methods
Patients and Settings
The Perioperative Rehabilitation in Operation for LUng CAncer (PROLUCA) feasibility study included 40 patients. The inclusion criteria were the following: biopsy-proven diagnosis of NSCLC, scheduled for surgery with curative intention, at least 18 years of age, World Health Organization performance status 0 to 2,16 resident of the City of Copenhagen or a surrounding municipality, able to read and understand Danish, and approval by the primary surgeon. The exclusion criteria were the following: presence of met-astatic disease or surgical inoperability, diagnosis of lung
cancer not verified pathologically, severe cardiac disease, and contraindications to maximal exercise testing as recom-mended by the American Thoracic Society and by exercise testing guidelines for cancer patients.17,18
Procedure
The study was conducted in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement for nonpharmacologic interventions and the World Medical Association Declaration of Helsinki.19,20 Written informed consent was obtained from all patients prior to initiation of the study procedure. The study was approved by the Danish National Committee on Health Research Ethics (File No. H-3-2012-028) and the Danish Data Protection Agency (File No. 2007-58-0015).
The study comprised a 4-arm, randomized feasibility design. Patients were referred from 2 medical departments to the Department of Cardiothoracic Surgery, Rigshospitalet.
Baseline assessment included physical tests and patient-reported outcomes and was performed at the Copenhagen Centre for Cancer and Health. HRQoL was assessed at the following 5 time points:
1. Baseline assessments completed as close to the time of diagnosis as possible
2. Presurgery assessments completed the day before surgery
3. Postintervention assessments completed 2 to 14 days after the last exercise session
4. Six-month assessments completed as close as pos-sible to 26 weeks after surgery
5. One-year assessments completed as close as possi-ble to 52 weeks after surgery
Group Allocation (Randomization)
Following the successful completion of baseline assess-ments, patients were randomized and allocated, on an indi-vidual basis, to 1 of the 4 exercise intervention groups, as described in the study protocol by Sommer et al.21 Around half of the patients initiated the postoperative exercise 2 weeks after surgery and the other half 6 weeks after surgery.
The intention-to-treat analysis included all randomized participants in their randomly assigned allocations. The intervention group assignment was not altered based on the participant’s adherence to the randomly allocated study arm. Patients who were lost to follow-up were included in the analysis (intention-to-treat).
Postoperative Exercise Training Protocol
The postoperative exercise intervention was a part of the rehabilitation services available at a rehabilitation center,
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described in Figure 1. Every participant was initially screened for rehabilitation needs using a professional rehabilitation guide covering the following topics: disease specific, social, network, relatives, psychological, existen-tial, diet, smoking, alcohol, physical activity, sexuality, sleep, and stress. The theoretical framework of the rehabilita-tion guide was based on World Health Organization on International Classification of Functioning,22 Bandura’s self-efficacy theory,23 and Miller’s motivational interviewing.24 The exercise intervention consisted of 24 group-based exercise sessions combined with 3 individual counseling sessions and 3 group-based lessons in health-promoting behavior. If the patients had special needs in terms of smoking cessation, nutritional counseling, or patient edu-cation, this was also offered as part of the rehabilitation. The postoperative exercise consisted of individually tai-lored, supervised strength exercise and group-based car-diorespiratory exercise twice a week (60 minutes/session) on nonconsecutive days for 12 weeks, for a total of 24 sessions.
Sommer et al15 describe the details of the exercise inter-vention and the physiological results of the PROLUCA fea-sibility study.
Adherence Considerations
To maximize adherence, several strategies were employed: telephone-based follow-up, free parking in front of the cen-ter, and remuneration for transport expenses. A high degree of scheduling flexibility allowed patients to perform tests at a convenient time to allow space for competing demands such as medical appointments, work, and family commitments.
Patient-Reported Outcomes
Patient-reported outcomes included HRQoL, symptoms and side effects, anxiety and depression, well-being, dis-tress, lifestyle, and social support, which were measured at 5 time points: baseline, presurgery, postintervention, and 6 months and 1 year after surgery. HRQoL was assessed using the integrated system of the European Organization for Research and Treatment in Cancer (EORTC), which is often used in cancer patients participating in international clinical trials and devised through collaborative research. The EORTC QLQ (Quality of Life Questionnaire) C30 assesses patient symptoms and HRQoL in cancer patients.25 Symptoms and side effects were further assessed using the EORTC-QLQ-LC (Lung Cancer) 13, which is an additional page to the EORTC-QLQ specifically designed to cover a wide range of lung cancer patients varying in disease stage and treatment modality.26 EORTC measures single items, and the scoring scale ranges from 0 to 100. A high score for a functional scale represents a high/healthy level of func-tioning, and a high score for the global quality of life repre-sents a high HRQoL. However, a high score for a symptom scale/item represents a high level of symptomatology or problems.25,26 A difference of 5 to 10 points in the scores represents a small change, 10 to 20 points a moderate change, and greater than 20 points a large clinically signifi-cant change from the patient’s perspective.27
HRQoL was also assessed using the Functional Assessment of Cancer Therapy–Lung (FACT-L) scale. FACT-L contains 4 subscales for physical well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), and functional well-being (7 items), while
Diagnosis Follow-up
Cancer patients´ course of disease
Cancer treatment
Contact personA physiotherapist, nurse, or dietician is assigned to each patient throughout the program
Assessment interviewAn individualized rehabilitation program is planned jointly by the patient and contact person
Last follow-up interviewFocus on completion of program
Referral Completion
Rehabilitation program at Copenhagen Centre for Cancer and HealthMultidisciplinary intervention programAssessment
Physical activity Strength and cardiovascular training, stability training, nature activities, running teams
Dietary guidance Individual and group counseling, cooking
Social counselingIndividual counseling, rights, return to work
Patient educationDisease/medication, life-style issues, coping skills, experience sharing
Other optionsSmoking cessation, meetings for relatives, counseling, yoga and mindfulness provided by the Danish Cancer Society
Completion interviewFocus on adherence to changed life style
Rehabilitation needs based on screening for:•Physical activity•Smoking•Diet•Alcohol•Disease and treatment
specific symptoms •Social, existential and
psychological challenges•Relatives•Network•Sexuality•Sleep•Stress
Figure 1. Rehabilitation services available from diagnosis to follow-up at the rehabilitation center.
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4 Integrative Cancer Therapies
the 7-item FACT-L lung cancer subscale (LCS) assesses symptoms commonly reported by lung cancer patients (eg, shortness of breath, loss of weight, tightness in chest). The trial outcome index (TOI) is derived by adding scores on the physical well-being and functional well-being subscales to the lung cancer subscale.28 All FACT-L items are rated on a 5-point Likert-type scale ranging from 0 = “Not at all” to 4 = “Very much,” and scores range from 0 to 24 (emotional well-being), 0 to 28 (other 4 subscales), 0 to 84 (TOI), and 0 to 136 (total score).29,30 Higher scores represent better quality of life or fewer symptoms.28 General well-being was assessed using the 36-item Short Form Health Survey (SF-36) version 1, standard recall (4 weeks). SF-36 includes 8 scales measuring general health with 2 summary scales: physical and mental component scales.28,31 Psychological well-being was assessed using the Hospital Anxiety and Depression Scale (HADS), which has 14 items designed to measure general anxiety and depression in patients with physical illness.32 The National Comprehensive Cancer Network (NCCN) Distress Thermometer is a validated measure of distress and consists of a single item, with responses ranging from 0 to 10.33 The NCCN Distress Thermometer was used to assess distress, and the Multidimensional Scale of Perceived Social Support (MSPSS) was used to assess social support. MSPSS is a 12-item scale that uses a 7-point Likert-type scale ranging from 1 = “Very strongly disagree” to 7 = “Very strongly agree.” The scale yields 3 subscale scores for family, friends, and significant others, in addition to a total score, which is verified with a confirmatory factor analysis.34 In addition to the MSPSS questionnaire, 7 questions on sup-port from other cancer patients were collected. In other can-cer studies, the above-mentioned validated instruments were found appropriate and easy to administer.33,35-37
Statistical Analysis
Repeated-measures analysis of variance was performed using the MIXED Procedure, SAS/STAT software, version 9.3. The clustered nature of the data was taken into account by specifying a heterogeneous autoregressive (1) covariance structure. The overall effect of time was evaluated using an F test. Estimated scale mean scores are reported as mean with corresponding 95% confidence intervals (CIs) and compared to reference data when available. We used Danish reference data for the EORTC QLQ-C3038 and the SF-36.39 For smoking, alcohol, and physical activity habits we used logistic, Poisson, and multinomial logistic regression mod-els, respectively. The clustered nature of the data was taken into account using generalized estimating equations,40,41 as implemented in the GENMOD procedure in SAS/STAT software, version 9.3. Wald tests were used to evaluate changes over time.
Results
Study Population and Baseline Characteristics
A total of 180 patients referred for surgery were screened for eligibility, 124 of whom were eligible. Forty patients (32%) were included and randomized in accordance with the flow chart shown in Figure 2. Table 1 shows the charac-teristics of the 40 patients included in the study. The mean age was 68 years, 15% were currently employed, and the majority were retired (Table 1). The most frequent comor-bidities were hypertension, dyslipidemia, rheumatic dis-ease, and chronic obstructive pulmonary disease (COPD). Five patients had no comorbidity, and 16 patients had more than 2 comorbidities. At baseline, 70% were ex-smokers and 25% were currently smoking. Eleven patients reported that their level of alcohol consumption was above 7 units per week for females and above 14 units per week for males, which is the maximum weekly intake recommended by the Danish National Board of Health. Five patients reported they were sedentary before time of diagnosis. Nine patients (22%) underwent thoracotomy, and 31 (78%) patients had video-assisted thoracic surgical resection (VATS). Thirteen (33%) received postoperative (adjuvant) chemotherapy. The extent of resection was lobectomy (83%), pneumonec-tomy (2%), bilobectomy (5%), wedge resection (8%), and VATS segmental resection (2%).
The 2 most frequent reasons given by patients for not attending the study were either logistical problems or con-cerns about the coming surgery (Figure 2).
Dropouts
Eleven patients dropped out during the intervention, pri-marily due to lack of motivation or due to side effects to adjuvant chemotherapy. There was no difference between completers and dropouts regarding demographic data, stage of disease, or type of surgery.
Changes in Health-Related Quality of Life
The FACT-L emotional well-being showed a statistically significant improvement across the 5 time points (Figure 3A, P < .0001). The results from FACT-L lung cancer sub-scale, TOI, and the total score also showed a statistically significant improvement across the 5 time points (Figure 3B, P = .0421; Figure 3C, P = .0376; and Figure 3D, P = .0163). The EORTC-QLQ-C30 functional scales showed increasing levels of global quality of life and emotional well-being (Figure 4A, P = .0032, and Figure 4B, P = .0006). Results from the SF-36 showed improvements for the mental health component score (Figure 5A, P = .0004) and for the domain scores for role physical function, vital-ity, and mental health during the study period (Figure 5B,
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P = .0072; Figure 5C, P = .0110; and Figure 5D, P = .0001, respectively). The SF-36 domain bodily pain showed no overall statistically significant difference between the 5 time points (P = .1069), but post hoc comparisons indi-cated that scores 6 months and 1 year after surgery were higher than the baseline scores (7.3 and 7.6 points, respectively).
Changes in Symptom Scales
Results for the 5 time points in EORTC symptom scales showed no differences across time points in any of the reported symptoms (results not shown).
Changes in Level of Anxiety, Depression, and Distress
Results from HADS and Distress Thermometer demon-strated a significant reduction in the level of anxiety, depression and distress, role of distress during the study period, and the greatest reduction was found 6 months after surgery (Figure 6A, P = .0003; Figure 6B, P = .0062; Figure 7A, P = .0006; and Figure 7B, P = .0005).
Changes in Perceived Social Support
The changes in perceived social support showed no overall statistically significant difference between the 5 time points in any of the subscales for support from significant others, family, friends, or in the total sum across the 12 items (results not shown). The baseline scores for all MSPSS sub-scales were high at baseline (Table 1) and during the study (results not shown). Changes in perceived support from other cancer patients were statistically significant during the study period (Figure 8; P < .0001).
Changes in Smoking, Alcohol, and Physical Activity Habits
The changes in smoking, alcohol and physical activity hab-its showed a reduction in the number of patients currently smoking from 25% at baseline to 5% after the intervention, followed by an increase to 12% one year after surgery. These percentages did not differ significantly (Wald test χ2 = 8.47, degrees of freedom (df) = 4, P = .0759, P for trend .0579). A similar pattern was seen in connection with alcohol consumption. At baseline, 28% consumed more alcohol than recommended by the Danish National Board
Total number screened n=180
Number completing preoperative exercise n=12 (12/18=67%)
Number completing postoperative exercise n=29 (29/40=73%)
Completed follow-up at week 26, n=26 Completed follow-up at week 52, n=28
Total number eligible n=124
Total number randomized n=40 (40/124=32%)
Non-eligible patients n=56
Dropped out (n=11) Reasons: Lack of motivation (n=4) Side effects to adjuvant chemotherapy (n=3) Other (n=2) Hospitalization (n=1) Died (n=1)
Not included (n=84)
Reasons: Logistical (n=35) Had too much to think about (n=35) Already exercising (n=6) Did not believe in effect (n=6) Missed for recruitment (n= 2)
Figure 2. Patient flow chart for Perioperative Rehabilitation in Operation for LUng CAncer (PROLUCA) feasibility study.
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of Health. This amount was reduced to 7% postinterven-tion, followed by an increase to 14% one year after surgery. Comparing the number of drinks per week using Poisson regression did not indicate significant differences across the 5 time points (Wald test χ2 = 4.33, df = 4, P = .3634, P for trend .1371). Physical inactivity dropped from 15% at baseline to 4% one year after surgery. Comparing the dis-tribution of the ordinal variable in multinomial logit regres-sion models adjusted for the level 3 months before diagnosis did not indicate significant differences across the 5 time points (Wald test χ2 = 8.10, df = 4, P = .0881, P for trend .6985).
Discussion
This feasibility study demonstrated that global quality of life and domains representing emotional or mental well-being improved significantly during the study period, from prior to surgery until 1 year after resection, in patients with NSCLC participating in rehabilitation.
Results from the EORTC-QLQ-C30 showed that global quality of life improved significantly during the study and to a level higher than the level in an age-matched Danish cohort.38 Braun et al found that, in patients with NSCLC, every 10-point increase in global quality of life was associ-ated with a 9% increase in survival.5 The present study found a 17-point increase in the domain global quality of life from baseline to 6 months after surgery and a 13-point
Table 1. Baseline Characteristics.
Variables Total N = 40
Age, years, median (range) 68 (36-85)Female, n (%) 24 (60%)Body mass index, kg/m2, mean (SD) 25 (5)Academic professional degree <3
years, n (%)17 (43%)
Smoking history Currently smoking, n (%) 10 (25%) Never smoked, n (%) 2 (5%) Ex-smoker, n (%) 28 (70%) Years smoking, mean (SD) 41 (15)Presence of comorbidity (5 patients had none) Hypertension, n (%) 15 (38%) Dyslipidemia, n (%) 9 (23%) Diabetes, n (%) 6 (15%) Atrial fibrillation, n (%) 2 (5%) COPD, n (%) 8 (20%) Rheumatic diseases, n (%) 12 (30%) Other type of cancer, n (%) 6 (15%) Depression, n (%) 4 (10%) Medication, number of drugs,
median (range)3 (1-6)
FACT-L health-related quality of life scores, mean (SD)a
Physical well-being 24.6 (3.7) Social/family well-being 22.6 (5.8) Emotional well-being 17.0 (5.1) Functional well-being 19.1 (7.3) FACT-L lung cancer subscale 20.8 (5.0) Trial outcome index 64.9 (14.0) Total score 104.7 (19.9)EORTC-QLQ functional scales, mean (SD)b
Global quality of life (global health status)
65.6 (24.0)
Physical functioning 88.0 (17.4) Role functioning 90.2 (17.8) Emotional functioning 75.6 (20.3) Cognitive functioning 88.9 (16.8) Social functioning 92.7 (15.2)SF-36 health-related quality of life scores, mean (SD)b
Physical component score 50.3 (10.2) Mental component score 43.7 (13.2) Physical function 82.3 (21.1) Role physical function 65.3 (42.3) Bodily pain 75.9 (19.1) General health perception 60.6 (17.2) Vitality 61.0 (25.8) Social functioning 85.5 (18.7) Role emotional 62.2 (37.8) Mental health 66.5 (21.9)MSPSS, mean (SD)c
Significant other 6.2 (1.4) Family 6.2 (1.4) Friends 6.0 (1.4)
Variables Total N = 40
Total MSPSS 6.2 (1.2) Support from other patients with
cancer2.5 (1.6)
HADS, mean (SD)d
Anxiety 5.8 (5.1) Depression 6.2 (3.1)NCCN Distress Thermometer, mean (SD)e
Distress 4.4 (4.0) Distress role 3.6 (3.5)
Abbreviations: COPD, chronic obstructive pulmonary disease; EORTC-QLQ, European Organization for Research and Treatment in Cancer–Quality of Life Questionnaire; FACT-L, Functional Assessment of Cancer Therapy–Lung; HADS, Hospital Anxiety and Depression Scale; MSPSS, Multidimensional Scale of Perceived Social Support; NCCN, National Comprehensive Cancer Network; SF-36, Short-Form Health Survey; SD, standard deviation.aScore range 0 to 24, 0 to 28, 0 to 84, 0 to 136. High scores indicate good health-related quality of life or fewer symptoms.bScore range 0 to 100. High scores indicate good health-related quality of life.cScore range 0 to 7. High scores indicate high level of support.dScore range 0 to 21. High scores indicate high levels of anxiety and depression.eScore range 0 to 10. High scores indicate high levels of distress and role of distress.
Table 1. (continued)
(continued)
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increase from baseline to 1 year after surgery. According to a study by Osoba, a difference of 5 to 10 points represents a small significant change, 10 to 20 points a moderate change, and greater than 20 points a larger clinically significant change from the patient’s perspective.27 Therefore, the improvement found in the present study is interpreted as a moderate change.
For 178 patients operated for NSCLC with no subse-quent recurrence, Kenny et al found a substantial initial deterioration in the physical dimensions and global quality of life, with an improvement to baseline levels between hospital discharge and 2 years after diagnosis.42 The study
by Kenny et al was, in contrast to this study, not designed to evaluate participation in rehabilitation but examined the role of position emission tomography in preoperative assessment.42 The findings in the present study showed an improvement from baseline to postintervention, with an additional increase 6 months after surgery, in global quality of life, which may be interpreted as an effect of the present rehabilitation program, although the lack of a control group weakens the conclusion.
In the present study, results from the SF-36 demonstrated that the mental health component score and the scores from the following domains: role physical function, vitality, and
Figure 3A. Functional Assessment of Cancer Therapy–Lung (FACT-L) Emotional well-being.Score range 0 to 24. High scores indicate good health-related quality of life. CI, confidence interval.
Figure 3B. Functional Assessment of Cancer Therapy–Lung (FACT-L) Lung cancer subscale.Score range 0 to 28. High scores indicate low level of symptoms reported. CI, confidence interval.
Figure 3C. Functional Assessment of Cancer Therapy–Lung (FACT-L) Trial Outcome Index.Score range 0 to 84. High scores indicate good health-related quality of life. CI, confidence interval.
Figure 3D. Functional Assessment of Cancer Therapy–Lung (FACT-L) Total score.Score range 0 to 136. High scores indicate good health-related quality of life. CI, confidence interval.
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mental health improved significantly during the study period. The domain bodily pain showed that the patients experienced less pain over time during the study period and also less pain compared to an age-matched Danish cohort.39 Brocki et al confirm this improvement postintervention and also found an effect in the bodily pain domain related to a
supervised outpatient exercise program. They also found a trend in favor of the intervention for role physical function and the physical health component score.43 In contrast to our findings, the tendency in the study of Brocki was reversed at 12 months after surgery, with the control group presenting overall slightly better measures.43
Figure 4A. European Organization for Research and Treatment in Cancer–Quality of Life Questionnaire (EORTC-QLQ) Global quality of life.Score range 0 to 100. High scores indicate good health-related quality of life. CI, confidence interval.
Figure 4B. European Organization for Research and Treatment in Cancer–Quality of Life Questionnaire (EORTC-QLQ) Emotional functioning.Score range 0 to 100. High scores indicate good health-related quality of life. CI, confidence interval.
Figure 5A. Short Form Health Survey (SF-36) Mental component score.Score range 0 to 60. High scores indicate good health-related quality of life. CI, confidence interval.
Figure 5B. Short Form Health Survey (SF-36) Role physical function.Score range 0 to 100. High scores indicate good health-related quality of life. CI, confidence interval.
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Brunelli et al found that patients with NSCLC were below the norm population in the physical health compo-nent score. In addition, their study showed a decline in the same score 1 month after surgery returning to preoperative values 3 months after surgery.44
In contrast to the findings of Brunelli et al, the results from this study showed that the physical health component
score was higher at baseline and 1 year after surgery com-pared to an age-matched Danish cohort.39 A reasonable explanation could be selection bias, as we cannot rule out that patients participating in this study represent a group with better physical fitness than the group refusing to par-ticipate. The mental health component score improved form baseline level below the norm population to the same level as the norm population 6 months after surgery. Moller and Sartipy found in a cohort of patients with NSCLC that mental health component summary scores below the mean
Figure 5C. Short Form Health Survey (SF-36) Vitality.Score range 0 to 100. High scores indicate good health-related quality of life. CI, confidence interval.
Figure 5D. Short Form Health Survey (SF-36) Mental health.Score range 0 to 100. High scores indicate good health-related quality of life. CI, confidence interval.
Figure 6A. Hospital Anxiety and Depression Scale (HADS) Anxiety.Score range 0 to 21. Low scores indicate low level of anxiety. CI, confidence interval.
Figure 6B. Hospital Anxiety and Depression Scale (HADS) Depression.Score range 0 to 21. Low scores indicate low level of depression. CI, confidence interval.
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of the age- and gender-matched normal population were associated with a 3-fold increase in the risk of death.6
Results from FACT-L showed that emotional well-being improved significantly during the study. The improvement in emotional well-being postintervention is similar to the effect found in patients with advanced lung cancer partici-pating in rehabilitation.45
The improvement in TOI (5 points) and lung cancer sub-scale (2 points) are according to Cella et al clinically mean-ingful for patients with NSCLC.46 Cella and colleagues demonstrated that a 2- to 3-point change in LCS and a 5- to 6-point change in TOI was a clinically meaningful change
in patients with NSCLC.46 As this feasibility study is under-powered, no conclusions can be drawn.
As only 33% of the patients (n = 13) were treated with chemotherapy, it is not possible in this study to evaluate the influence of chemotherapy on HRQoL.
According to Zigmond and Snaith, HADS anxiety and depression subscale scores can be classified as normal (0-7), mild (8-10), moderate (11-14), or severe (15-21).32 The lev-els of anxiety and depression in the present study are there-fore judged to be normal, but the level of anxiety still showed a decrease in the anxiety score between baseline and 6 months after surgery, which reversed between 6 months and 1 year after surgery without reaching the baseline level. This tendency was not observed in levels of depression.
Results from distress (NCCN Distress Thermometer) showed the same pattern as HADS regarding anxiety, the scores showing parallel fluctuations. This indicates a cor-relation between anxiety and distress, which was also found in a study by Bidstrup et al.33 The present study showed that the level of anxiety decreased 6 months after surgery, but reversed 1 year after surgery without reaching the baseline level. This pattern was not found in patients with COPD, where the level of anxiety increased with time.47
According to parameters from a study by Zimet et al, con-cerning social support, the results from the present study can be interpreted as high social support at baseline and during the study period.48 Zimet et al found that a mean score rang-ing from 1 to 2.9 represents a low level of support, a score of 3 to 5 moderate support, and 5.1 to 7 high support.48 This is in contrast to a Danish study by Quist et al that involved a similar intervention where social well-being decreased.45 The patients participating in their study had advanced lung can-cer, and their condition and disease stage differ from the
Figure 7A. National Comprehensive Cancer Network Distress Thermometer Distress.Score range 0 to 10. Low scores indicate low level of distress. CI, confidence interval.
Figure 7B. National Comprehensive Cancer Network Distress Thermometer Distress role.Score range 0 to 10. Low scores indicate that the distress plays a low role. CI, confidence interval.
Figure 8. Multidimensional Scale of Perceived Social Support (MSPSS) Support from other cancer patients.Score range 0 to 7. Low scores indicate low social support from other cancer patients. CI, confidence interval.
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Sommer et al 11
patients participating in the present study. The significant increase in support from other cancer patients during our study could hypothetically have a connection to the improve-ment in emotional well-being and reflects the value of estab-lishing a social network. A qualitative study by Missel et al, in the present population, found that group training had social benefits, such as patients experiencing a sense of belonging and that exercising with others in a similar circumstance is meaningful due to the sense of community created.49
The level of patients reporting being sedentary dropped from 15% to 4% during our study. Granger et al found that 40% of patients with NSCLC did not meet physical activity recommendations at time of diagnosis and after 6 months; without a specific exercise intervention, these patients experienced a decline in physical activity, functional capacity, and strength compared to healthy individuals.50 Cavalheri et al found that patients with NSCLC treated with lobectomy were more sedentary than healthy age-matched controls.51 Results from the present study on smoking and alcohol habits showed a decrease in the num-ber of smokers and patients with an intake above the rec-ommended amount from baseline to postintervention, but this effect reversed 1 year after surgery without reaching the baseline. The present changes in smoking, alcohol, and physical activity habits were not statistically significant, but the results are of clinical importance and they underline the need for optimizing maintenance from rehabilitation.
Strengths and Limitations
The strengths of this study are the use of well-validated HRQoL questionnaires and the analysis of the consumption of alcohol and tobacco from the time of diagnosis to 1 year after surgery.
A methodological weakness is the low number of par-ticipants and the absence of a control group, since it leaves out the possibility of concluding on the effect of the intervention.
The fact that only 32% of the eligible patients participated in the present study limits the generalization of the results, as the patients might not be representative of the population operated for NSCLC in Denmark. The low recruitment rate could also affect the results, because participation in the study could be related to patients with better performance sta-tus and physical fitness compared with the group not partici-pating. However, a comparison of the baseline characteristics of the patients in the present study with cohort studies in patients with NSCLC reveals similarities regarding age, sex, pulmonary function, and comorbidities.52,53
Conclusion
This feasibility study demonstrated that global quality of life, mental health, and emotional well-improved significantly
during the study, from time of diagnosis until 1 year after resection, in patients with NSCLC participating in rehabilita-tion. There was a reduction in distress and anxiety and smok-ing and alcohol habits from baseline to after the intervention, followed by an increase 1 year after surgery, which under-lines the need for continued rehabilitation initiatives. The clinical implication of these results is awareness from the health care professionals in supporting patients with operable lung cancer to maintain the achieved lifestyle changes throughout life.
Acknowledgments
The authors would like to thank the patients who participated in this study and the staff at Copenhagen Centre for Cancer and Health for their work during the data collection. We would also like to acknowledge the staff at the collaborating hospitals for their assistance during data collection.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is supported by grants from the Center for Integrated Rehabilitation of Cancer Patients (CIRE), which was established and is supported by the Danish Cancer Society and the Novo Nordisk Foundation. Funding has also been provided by Rigshospitalet, University of Copenhagen; the Faculty of Health and Medical Sciences, University of Copenhagen; and the City of Copenhagen. CopenRehab is also supported by a grant from the City of Copenhagen.
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Correction to Paper III
Figure 5A. will be replaced with this figure in the next edition of the Journal of Integrative
Cancer Therapy and the published article will be updated at the time of print issue.
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Journal Compilation © 2018 Foundation of Rehabilitation Information. ISSN 1650-1977This is an open access article under the CC BY-NC license. www.medicaljournals.se/jrm
doi: 10.2340/16501977-2292
REVIEW ARTICLEJ Rehabil Med 2018; 50: 236–245
EFFECT OF POSTSURGICAL REHABILITATION PROGRAMMES IN PATIENTS OPERATED FOR LUNG CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS
Maja S. SOMMER, MHS, PT1,2#, Maja E. B. STAERKIND, MHS, PT3#, Jan CHRISTENSEN, MSPT2,4, Jette VIBE-PETERSEN, MD1, Klaus R. LARSEN, MD, PhD5, Jesper H. PEDERSEN, MD, DMSc6 and Henning LANGBERG, MD, DMSc2,7
From the 1Copenhagen Centre for Cancer and Health, City of Copenhagen, 2CopenRehab, Section of Social Medicine, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, 3University Hospitals Centre for Health Research (UCSF), Rigshospitalet, 4Department of Occupational- and Physiotherapy, Copenhagen University Hospital, 5Department of Respiratory Medicine, Bispebjerg University Hospital, 6Department of Cardiothoracic Surgery RT, Rigshospitalet and 7Department of Public Health, Section of Social Medicine, University of Copenhagen, Copenhagen, Denmark. #These 2 authors contributed equally and should be considered as first authors.
Objective: To review the evidence concerning the ef-fects of postoperative exercise interventions on ex-ercise capacity and health-related quality of life fol-lowing resection for non-small cell lung cancer, and to review whether different initiation times of exer-cise produce different effects on exercise capacity. Data sources: Comprehensive literature search of MEDLINE, Embase, CENTRAL, CINAHL and PEDro.Study selection: Randomized controlled trials exami-ning the effects of exercise interventions were eli-gible for inclusion. Data extraction: Postoperative outcome measure-ments were extracted and the quality of evidence was graded using Grading of Recommendations As-sessment, Development and Evaluation (GRADE) Working Group.Data synthesis: Four randomized controlled trials were identified involving 262 participants. Short-term follow-up (12–20 weeks) showed significantly higher exercise capacity and physical component of health-related quality of life in the intervention gro-up (standardized mean difference (SMD) 0.48; 95% confidence interval (CI) 0.04–0.93) compared with the control group (SMD 0.50; 95% CI 0.19–0.82). There was no difference between the effect of late- and early-initiated exercise intervention. Conclusion: Exercise has a small-to-moderate effect at short-term follow-up on exercise capacity and the physical component of health-related quality of life in patients operated for lung cancer. The long-term effects of exercise capacity are unknown. Early-initi-ated exercise programmes (2 weeks post-operation) did not show an effect on exercise capacity. These findings should be interpreted with caution.
Key words: non-small cell lung cancer; exercise; health-re-lated quality of life.
Accepted Oct 5, 2017; Epub ahead of print Jan 25, 2018
J Rehabil Med 2018; 50: 236–245
Correspondence address: Maja S. Sommer, Copenhagen Centre for Cancer and Health, City of Copenhagen, Norre Allé 45, DK-2200 Co-penhagen, Denmark. E-mail: [email protected]; Maja E. B. Staerkind, University Hospitals Centre for Health Research (UCSF), Rigshospitalet, Blegdamsvej 9, DE-2100 Copenhagen, Denmark. E-mail: [email protected]
Lung cancer is one of the most common malignancies worldwide, and the leading cause of cancer-related
death (1). Pulmonary resection is currently the most ef-fective curative treatment when non-small cell lung can-cer (NSCLC), stage I, II, IIIA, is diagnosed. Surgery is performed using either an open approach (thoracotomy) or minimally invasive video-assisted thoracoscopic sur-gery (VATS) (2). Improvements in earlier preoperative staging, better surgical techniques and more effective adjuvant treatment have enhanced survival (3). Lung cancer surgery is associated with morbidity, functional limitations and decreased quality of life (4).
As a result, evidence-based rehabilitation may be a key component to improve outcome and quality of life in these patients (4, 5). An emerging discipline in rehabilitation of lung cancer survivors, exercise inter-vention, is associated with benefits that may improve the health of long-term cancer survivors and extend survival (6).
Studies demonstrate lower levels of physical activity among individuals diagnosed with NSCLC compared with healthy individuals, yet the physical activity level decreases further during the first 6 months following diagnosis (7).
The increase in population of lung cancer survivors signifies the need to improve their health. Barriers for participating in rehabilitation and maintaining lifestyle changes are, for example, high symptom burden, such as side-effects to the adjuvant treatment, and high pre-valence of comorbidity, especially chronic obstructive pulmonary disease (COPD) (8).
Exercise initiated early in the treatment trajectory is found to be beneficial for operable lung cancer patients (9, 10). In a population diagnosed with myocardial infarction, early-initiated exercise in the acute phase has shown greater benefits on exercise capacity than is the case in exercise interventions initiated in a later treatment phase (11).
Systematic reviews investigating the effects of pre- and post-surgical exercise interventions in patients with NSCLC show that exercise may increase exer-cise capacity of people following lung resection for
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237Postsurgical rehabilitation for patients with lung cancer
NSCLC (6, 12, 13). However, to date, no systematic reviews have been done investigating the effects of post-surgical exercise interventions for patients with NSCLC focusing on high-quality evidence and only post-operative outcomes to eliminate the impact of the surgery (no pre-operative baseline measurements).
Furthermore, no previous reviews have focused on whether the effect would differ due to different initia-tion times for postoperative exercise in patients with NSCLC. The present review hypothesized that early initiation of exercise (within 2 weeks) following lung resection for NSCLC would increase the effect on exer-cise capacity compared with later initiation of exercise.
The primary objective was to systematically review the literature for the effect of postoperative exercise interventions on exercise capacity in patients fol-lowing lung resection for NSCLC. A secondary aim was to review the effect of exercise interventions on health-related quality of life (HRQoL) and to determine whether different initiation times of exercise either enhanced or decreased exercise capacity in patients following lung resection.
METHODSThe protocol for this systematic review was registered in the PROSPERO database (registration number CRD42016027412). The Cochrane Handbook for Systematic Reviews of Interven-tions (14) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines (15) were applied during preparation of this review.
Inclusion criteria
Randomized controlled trials (RCT) assessing the effects of postoperative exercise interventions in patients undergoing resec-tion for NSCLC, in which participants were allocated to receive exercise compared with a control group, were included. Studies and abstracts published in English, one of the Scandinavian langu-ages, or German were eligible for inclusion. Inclusion criteria were trials with participants receiving any type of lung resection performed with VATS or thoracotomy procedures. To avoid com-parison of effect measures in different populations, trials were included only if at least 50% of the population had resectable NSCLC. Trials were included if the interventions comprised any type of exercise involving bodily movements produced by skeletal muscles (aerobic exercise, resistance exercise, ambulation or mobility exercise) initiated within 1 year after lung resection.
Supervised and/or unsupervised exercise performed individu-ally or in groups were also eligible intervention criteria. Type, intensity, frequency and duration of the exercise interventions were not a constraint, but were recorded where possible. Control groups were considered eligible if they contained non-interven-tion control, usual care, waiting list control or add-on treatments.
Outcomes
VO2peak is considered the gold standard for the measurement of cardiorespiratory fitness and 6MWD is often used in pulmonary rehabilitation programmes to quantify exercise capacity, both
recommended for use in clinical oncology research (16–19). The primary outcome of the present review was any measure of maximum exercise capacity (16). Exercise capacity measures included peak oxygen consumption (VO2peak) and 6-minute walk distance (6MWD), measured as primary or secondary outcomes in the included studies.
The secondary outcome of interest was HRQoL assessed by 1 of the 3 most commonly used questionnaires for thoracic surgery patients: Generic 36-Item Short Form Health Survey (SF-36) (20), cancer-specific European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C-30) (21), and the disease-specific patient-reported outcome Functional Assessment of Cancer Therapy-Lung (FACT-L) (22). The European Society of Thoracic Surgeons defines these ques-tionnaires as the most appropriate for thoracic surgery patients.
Only postoperative outcome measurements were extracted, in order to examine the effect of postoperative exercise eliminating the impact of surgery and to compare effect sizes across studies. The inclusion criteria are summarized in Table I.
Data sources
A Comprehensive literature search of MEDLINE, Embase, CENTRAL, CINAHL and PEDro. The literature search matrix used for MEDLINE (shown in Appendix SI1) was adapted for use in the other databases (search strategies shown in Appendix SV1). The Search strategy focused on 2 overall clusters: NSCLC and rehabilitation, with their associated synonyms, combined with AND, as shown in Appendix SI1. No limitations were used in the electronic searches to avoid unintended exclusion of relevant trials.
In order to identify additional trials all reference lists of all primary studies and review articles were screened. Experts in the field of exercise and NSCLC were contacted in order to identify unpublished research. A search was also carried out of clinicaltrials.gov to identify ongoing, as yet unpublished, trials.
Selection of studies
All references identified were imported into the web-based software platform covidence.org. Selection of trials, risk of bias assessment, and extraction of data were managed with this software. Two review authors (MB, MS) independently
Table I. Inclusion criteria
DesignRCT
Participants> 18 years oldBoth sexes50% with NSCLCUndergoing any type of lung resectionAdjuvant chemotherapy or not
InterventionAerobic exerciseResistance trainingAmbulationMobility exercise
Outcome measuresExercise capacityHRQoL
RCT: randomized controlled trial; NSCLC: non-small cell lung cancer; HRQoL: health-related quality of life.
1http://www.medicaljournals.se/jrm/content/?doi=10.2340/16501977-2292
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238 M. S. Sommer, M.E.B Straerkind et al.
screened titles and abstracts, after which full-text screening was undertaken using the search strategy to determine eligibility for inclusion. Their decisions were recorded and disagreements were resolved by consensus.
Data extraction and management
Two review authors (MB, MS) independently extracted data using a predefined form based on the Cochrane Collaboration’s checklist of items to consider in data extraction (14). Data inclu-ded details of the trials, participant characteristics and results at postoperative time points. Disagreements on extraction of data were resolved by discussion.
Two review authors (MB, MS) independently assessed the risk of bias of all included trials, evaluated as either high, low or unclear risk of bias using the Cochrane Collaboration’s tool for assessing risk of bias (14). High risk of bias indicated that there was a high risk that the results would either overestimate or underestimate the true intervention effect, while low risk of bias indicated the opposite. Unclear risk of bias denoted either a lack of information or uncertainty concerning the potential of bias. Disagreements were resolved by discussion, or when necessary, a third review author (JC) was consulted and agreement reached.
Statistical analyses
For continuous outcomes standardized mean differences (SMD) and the corresponding 95% confidence intervals (95% CI) were used in the analysis. To calculate the SMDs the mean change scores and the corresponding standard deviations (SDs) were ex-tracted from the included trials when these were reported. Where mean change scores and/or SDs of the mean change scores were not applied, they were calculated based on the baseline and fol-low-up means and SDs, as recommended in the Cochrane Hand-book (14). The calculated SDs of the mean change scores from baseline were estimated by imputing a correlation coefficient in the formula below to allow the use of paired data (23, 24): SDchange=√SD2
baseline + SD2follow-up– (× corr × SDbaseline × SDfollow-up)
Correlation coefficients were used in the calculation of SDs of mean change scores in the following outcomes: VO2peak r = 0.927 (25), 6MWD r = 0.93 (19), SF-36 physical and mental component scores (26) and EORTC QLQ-C30 physical functio-ning score r = 0.85 (27).
If there was any discrepancy between the reported mean change scores and the stated baseline, and follow-up data were identified in an article, the mean change scores were also cal-culated based on the above-mentioned formula.
Cohen’s guidelines for interpreting the magnitude of SMD were followed: small SMD = 0.2; medium SMD = 0.5; and large SMD = 0.8 (28).
Authors of the reviewed trials were contacted to provide details of missing data. If the trial authors could not provide the requested information or were unable to comply with the request within 1 month, the review process continued without the information. When baseline and/or follow-up means and SDs were not published, the authors were contacted. Missing indivi-duals from the reported results were recorded, where possible, and results from intention-to-treat analyses were prioritized in the analysis of this review.
Clinical heterogeneity was evaluated by examining diver-sity in patient populations (e.g. age, resection degree, and comorbidities) and exercise interventions (e.g. type, intensity, frequency, duration) among the trials. In addition, the percentage of the variability in effect estimates due to heterogeneity was
evaluated using the I-squared test (I2), which is suitable in this review because it is independent of the numbers of studies. The interpretation of I2 is that a higher percentage indicates statistical heterogeneity, with tentative limits as “low” at 25%, “moderate” at 50% and “high” at 75%, considered substantial heterogeneity above 50% (29). A random-effects model, using the method of DerSimonian & Laird (30), was chosen if the clinical heterogeneity or I2 was evaluated to be high.
The follow-up closest to 12 weeks was designated as short-term and a long follow-up exceeding 6 months was designated as long-term.
A sensitivity analysis was conducted to assess the effect of trials initiating exercise interventions early (within the first 2 weeks after lung resection) compared with the effect of trials initiating exercise interventions later than 2 weeks after lung resection. This analysis was conducted on short-term outcomes. The 2-week time limit was a pragmatic approach based on clini-cal reflections on tissue healing and when stressing the operation wound by exercising would be safe. The purpose of this sensi-tivity analysis was to aid in identifying the optimal time-point to initiate postoperative rehabilitation after lung resection in patients with NSCLC. Since no evidence was available to guide this decision, a thoracic surgeon specialist made the assessment. Outcomes included in the “summary of findings” table were exercise capacity and HRQoL domains. Quality of evidence was assessed for each outcome by grading evidence according to the Grade of Recommendation, Assessment, Development and Evaluation Working Group (31).
Statistical analyses and forest plots were generated in Stata-Corp 2013, Stata Statistical Software: Release 13 (StataCorp LP, College Station, TX, USA). Risk of bias summary and graphs were generated with Review Manager software (RevMan), version 5.3, Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014. The summary of findings listed in Table II was conducted with GRADEpro GDT (GRADEpro Guideline Development Tool software, McMaster University, 2015 (developed by Evidence Prime, Inc.)
RESULTS
Electronic databases were searched on 17 February 2016 and resulted in a total of 6,191 hits: 1,641 from MEDLINE, 3,291 from Embase, 270 from the Cochra-ne Central Register of Controlled Trials (CENTRAL), 970 from CINAHL and 19 from PEDro. The number of duplicates was 1,661, resulting in 4,530 unique articles. Based on the title and abstract, 4,464 articles were excluded, resulting in 66 articles read in full text. Of these, 62 studies were excluded as they did not meet the inclusion criteria. The present review included 4 RCTs involving 262 participants (32–35). Three of the studies randomized the participants into 1 of 2 groups: an exercise intervention or a control group (32–34). The fourth study randomized the participants into 1 of 3 groups: exercise intervention 1, exercise intervention 2 or a control group (35).This study was divided into 2 studies in the analyses, in which each intervention group was compared with half the control group (14).
Twelve studies were in a language other than those listed in our criteria and 3 had missing data. The first
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239Postsurgical rehabilitation for patients with lung cancer
of the last-mentioned studies was contacted, but it was unable to provide postoperative measurements of exercise capacity (36); the second was a conference article that was insufficient due to low completion of the intervention and a high number of missing data (37); and the third was unable to provide the missing data on exercise capacity and HRQoL (38). Fig. 1 presents a flowchart of the search process based on the PRISMA template (15). Details of the excluded references are shown in Appendix SII1.
The studies, based in the UK, Denmark, Belgium and Norway, were published in 2011–2015. Two of the studies conducted the interventions in a hospital setting after discharge (33, 35), while participants in one study exercised during admission with subsequent home training (32). In the fourth study the intervention was conducted in local fitness centres after discharge (34). Fig. 1. Study flow diagram. RCT: randomized controlled trial; NSCLC:
non-small cell lung cancer.
Table II. Summary of findings for main comparisons
Exercise training compared with usual care for patients with non-small cell lung cancer (NSCLC) undergoing lung resection
Patient or population: patients with NSCLC undergoing lung resection Setting: varied Intervention: exercise training Comparison: usual care
Outcomes
Anticipated absolute effects* (95% CI)
Relative effect (95% CI)
Number of participants (studies)
Quality of the evidence (GRADE) Comments
Risk with usual care
Risk difference with exercise training
Exercise capacity – short term Assessed with: VO2peak and 6MWD Follow-up: range 12–20 weeks
– SMD 0.47 SD higher (0.07 higher to 0.88 higher)
– 234 (4 RCTs)
⨁⨁◯◯ LOWa,b,c
Sensitivity analysis: no effect of early-initiated exercise intervention (within 2 weeks post-surgery) on exercise capacity in the short-term (1 study only) (SMD 0.09; 95% CI –0.57 to 0.74)
Exercise capacity – long term Assessed with: 6MWD Follow-up: 1 year
– SMD 0.09 SD higher (0.44 lower to 0.61 higher)
– 56 (1 RCT)
⨁⨁◯◯ LOWb,d
HRQoL physical component – short term Assessed with: SF–36 and EORTC QLQ-C30 Follow up: range 12–20 weeks
– SMD 0.51 SD higher (0.22 higher to 0.80 higher)
– 145 (3 RCTs)
⨁⨁◯◯ LOWb,d,e
HRQoL physical component – long term Assessed with: SF-36 Follow-up: 1 year
– SMD 0.27 SD lower (0.78 lower to 0.25 higher)
– 58 (1 RCT)
⨁⨁◯◯ LOWb,d
HRQoL mental component – short term Assessed with: SF-36 Follow-up: range 10–20 weeks
– SMD 0.53 SD higher (0.78 lower to 1.83 higher)
– 97 (2 RCTs)
⨁◯◯◯ VERY LOWb,c,d,e
HRQoL mental component – long term Assessed with: SF-36 Follow-up: 1 year
– SMD 0.48 SD lower (1.01 lower to 0.04 higher)
– 58 (1 RCT)
⨁⨁◯◯ LOWb,d
*Risk in intervention group (and its 95% confidence interval (95% CI)) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; SMD: standardized mean difference; VO2peak: peak oxygen consumption; 6MWD: 6-minute walk distance; HRQoL: health-related quality of life; SF-36: 36-Item Short Form Health Survey; EORTC QLQ-C30: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to the estimated effect. Moderate quality: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimated effect. Very low quality: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimated effect. aLack of blinding of outcome assessment. bLack of blinding of participants and personnel. cHigh heterogeneity in effect estimates. dWide CI. eSelective reporting.⨁⨁⨁⨁High quality: We are very confident that the true effect lies close to the estimated effect. ⨁⨁⨁◯Moderate quality: We are moderately confident in the effect estimate. ⨁⨁◯◯Low quality: Our confidence in the effect estimate is limited. ⨁◯◯◯Very low quality: We have very little confidence in the effect estimate.
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All 4 studies included mainly participants who had undergone lung resection for NSCLC. Both sexes
were included and the mean age was over 60 years in all study groups. The majority of the participants went through open surgery (range 77–96%), and the lung cancer stages were equally distributed between control and exercise groups, except in one study, where 4 participants with stage IV NSCLC were randomized to the control group and none to the exercise group. For a summary of included studies see Tables III and IV.
Exercise interventions included a component with aerobic exercise and resistance training, except for intervention 2 in the 3-armed RCT, which included exercise and whole-body vibration (35).
The intervention components varied in intensity, fre-quency and duration across studies. The intensity of the
aerobic exercises, which consisted of either walking or biking, varied from 60% to 95% of maximum heart rate. The frequency of training varied from 1 session per week for 10 weeks (33) to 3 times a week for 12 (35) or 20 (34) weeks. The exercise interventions were initiated after 5 days (32), 3 weeks (33), 4–6 weeks (34) or within 8 weeks (35) following lung resection.
Baseline measurements in Arbane et al.’s study (32) were conducted pre-surgery, since the study initiated exercise pre-surgery until day 5 post-surgery. In order to rule-out variance due to operation outcomes we de-cided in the present study to use the first measurement on day 5 post-surgery as the “baseline” in the present review.
In addition, the results by Arbane et al. (32) showed no statistically or clinically effect of early exercise
Table III. Characteristics of included studies and participants
ReferenceNumber Ex/c
Mean age, years
Female (n)
Surgery (n)Thor/VATS
Additional treatment
Primary outcome
Secondary outcome Baseline Follow-up Analysis
Arbane 2011 et al. (32)
27/26 65.4/62.6 NR 51/2 NR EORTC QLQ-LC13c
6MWD Day 5 (originally pre-operative)
12 weeks Per protocol
Brocki 2014 et al. (33)
41/37 64/65 32/46 60/18 Any adjuvant: 16/18
SF-36 physical SF-36 mental
6MWD 3 weeks 4 months + 1 year
ITT
Edvardsen 2015 et al. (34)
30/31 64.4/65.9 33/28 51/10 Radio: 3/4 Chemo: 9/9
VO2peak (n = 30/31)
SF-36 physical (n = 14/16) SF-36 mental (n = 14/16)
4–6 weeks 20 weeks ITT: VO2peakPer protocol: SF-36 + EORTC7 (unpublished data)
Salhi 2015 et al. (35)
a24/24 b22/24
a63/64 b60/64
a6/6 b7/6
NR Radio: a3/1 b0/1 Radio+chemo: a3/5 b4/5
6MWD VO2peak EORTC QLQ-C30 physical functioning
Within 8 weeks 12 weeks ITT: 6MWDPer protocol: EORTC
aintervention group 1, bintervention group 2, cnot included in review due to absence of 2 postoperative measurements.c: control group; Ex: exercise group; NR: not reported; Thor: thoracotomy; VATS: video-assisted thoracoscopic surgery; Radio: radiotherapy; Chemo: chemotherapy; EORTC: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; SF-36: 36-Item Short Form Health Survey; VO2peak: peak oxygen consumption; 6MWD: 6-minute walk distance; ITT: intention-to-treat.
Table IV. Characteristics of included exercise interventions
ReferenceLength of intervention
Duration of session Exercise type Intensity Frequency
Supervised/unsupervised
Inpatient/outpatient
Group/individual Control group
Arbane 2011 et al. (32)
12 weeks (+5 days)
5–10 min per exercise
Aerobic (walking, marching, recumbent bike) + resistance (weights)
60–80% MHR 2 × /day Both Both Individual Monthly phone calls from research team, providing educationc
Brocki 2014 et al. (33)
10 weeks 5–15 min warm-up 10–20 min aerobic 10–15 min resistance 10 min cool down
Aerobic (walking, bike) + resistance (thera-band and own body weight) + cool down + (encouraged to exercise at home)
Warm-up: RPE 7–12 Aerobic: RPE 11–12 à 13–16 Resistance: 6–10 rep 1–2 sets Cool down: RPE 6
1 × /week Supervised Outpatient Group Instructed in home exercise: strength 2 × /week + daily 30 min walk/bike RPE 11–12
Edvardsen 2015 et al. (34)
20 weeks 60 min Warm-up + aerobic (walking uphill on treadmill), progressive resistance training (machines), inspiratory muscle training
Aerobic: 80–95% MHR Resistance: 6–12 RM
3 × /week Supervised Outpatient Individual No advice about exercise beyond general information from the hospital
Salhi 2015 et al. (35)
12 weeks 20 min aerobica+b
NR in resistancea
30 s for each vibration exerciseb
Aerobica+b (bike or treadmill) Resistancea (machines) Whole-body vibrationb (vibration platform)
Aerobica+b: 70% of Wmax Resistancea: 50% of 1 RM Vibrationb: 27 Hz
3 × /week Supervised Outpatient Group Discouraged to improve their exercise tolerance with professional help
aintervention 1, bintervention 2, ceducation content unknown. MHR: maximum heart rate; RPE: Borg Rating Perceived Exertion (range 6–20); REP: repetitions; RM: repetition max; Wmax: watt max.
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captured by the day 5 post-surgery measurement, even though the intervention group had a mean distance that was 28 m longer than the control group (measured at day 5 post-operatively). The minimal important dif-ference in the 6MWD in patients with lung cancer is 42 m (39).
The control groups received usual care, consisting of a monthly telephone call from the research team, which provided education (32), 1 h of individual instruction in home exercises (33), no advice beyond general information from the hospitals (34) and even discouraged to improving their exercise tolerance with professional help (35).
Exercise capacity was reported in all 4 studies, 2 of which reported VO2peak (34, 35) and 3 of which reported 6MWD (32, 33, 35). HRQoL was reported in 3 studies, 2 of which reported SF-36 in physical- and mental component scores (33, 34), and 1 of which reported the physical functioning score of the EORTC QLQ-C30 (35). One study did only have one measu-rements of HRQoL post-surgery, which is why that outcome was not extracted (32). All of the studies had collected a short-term follow-up at completion of their interventions, and 1 study had collected an additional long-term follow-up 1 year after baseline (33).
The overall assessment of risk of bias across the studies is presented in Fig. 2, while the risk of bias for the individual studies is presented in Appendix SIII1.
All of the studies reviewed were at high risk of performance bias because blinding of participants is difficult in exercise interventions. The majority of studies were at high or unclear risk of detection bias and reporting bias as the outcome assessors were not blinded and the relevant predefined outcomes were not evaluated due to lack of completion of outcome measures or no trial registry. The section called “Sum-mary of included studies” in Appendix SIV1 contains a detailed description of the assessment of risk of bias.
Effect of intervention
All meta-analyses were conducted using a random-effects model after assessment of clinical heterogeneity between studies, especially in exercise interventions.
VO2peak is considered the gold standard measure-ment of cardiorespiratory fitness research, therefore when both measurements were available VO2peak was chosen. Results at completion of the intervention periods, stated as short-term, showed a significantly higher exercise capacity in the intervention group compared with the control group (SMD 0.48; 95% CI 0.04–0.93), reflecting a small-to-moderate effect size (Fig. 3). The I2 was 61.6%, suggesting moderate variations between intervention effects. The study with a long-term follow-up showed no effect on exercise capacity after 1 year from baseline (SMD 0.09; 95% CI –0.44 to 0.61), the results are not illustrated.
The SF-36 physical component score was pooled in a meta-analysis with the EORTC QLQ-C30 physical functioning score. The physical component of HRQoL was significantly higher in the intervention group
Fig. 2. Risk of bias graph: review authors’ assessment of each risk of bias item presented as percentages across all included studies.
Fig. 3. Forest plot: effect of exercise capacity in exercise group vs control group (short term). SMD: standardized mean difference; 95% CI: 95% confidence interval.
Fig. 4. Forest plot: effect of the physical component of health-related quality of life (HRQoL) in exercise group vs control group (short term). SMD: standardized mean difference; 95% CI: 95% confidence interval.
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compared with the control group (SMD 0.50; 95% CI 0.19–0.82) in the short-term, reflecting a moderate effect size (Fig. 4). The I2 was 0%, suggesting a small variation between intervention effects.
According to the one study with long-term follow-up, there was no effect on the physical component of HRQoL in the long-term (SMD –0.27; 95% CI –0.78 to 0.25). The results are not illustrated in the present re-view. The SF-36 mental component score was reported in 2 studies and pooled in a meta-analysis. There was no effect on the mental component of HRQoL (SMD 0.53; 95% CI –0.78 to 1.83) in the short-term, nor at long-term follow-up (SMD –0.48; 95% CI –1.01 to 0.04). The results are not illustrated.
Only one study initiated exercise intervention early, within 2 weeks after surgery (32). This study showed no effect on exercise capacity in the short-term (SMD 0.09; 95% CI–0.57 to 0.74), as illustrated in Fig. 5. In 3 stu-dies that initiated exercise interventions later (33–35), > 2 weeks after surgery, in contrast, the exercise capacity was significantly higher in the intervention group com-pared with the control group in the short-term (SMD 0.58; 95% CI 0.07–1.09), reflecting a moderate effect size (Fig. 5). There was no difference between effect of late and early initiated exercise intervention. The I2 for exercise interventions initiated late was 65.6%, sug-gesting moderate variation between intervention effects.
The main findings and quality of the body of evi-dence for each result is presented in the summary of findings (Table II).
DISCUSSION
This meta-analysis showed that exercise improved ex-ercise capacity and the physical component of HRQoL in the short-term, but no beneficial effect was found
on the mental component of HRQoL. Only one study evaluated the long-term effects and found no effect on either physical capacity or HRQoL (33). Early-initiated exercise programmes, within 2 weeks after lung resec-tion, did not show an effect on exercise capacity. These findings must be interpreted with caution due to the heterogeneity of exercise programmes, methodological limitations, some significant risks of bias, small samp-les and the low number of studies included.
Overall completeness and applicability of evidenceAs exercise capacity appears to be a valuable prog-nostic indicator for patients with NSCLC, and the clinical finding that exercise capacity increases during exercise in patients following lung resection is highly important (40). Until now referral for rehabilitation fol-lowing lung resection has been based on an individual evaluation of rehabilitation needs. Numbers of referrals made is unpublished, but a survey from Australia and New Zealand reports that < 25% of patients are referred to pulmonary rehabilitation after lung resection (41). The inadequate level of referrals is due to the lack of well-designed studies to confirm the role of supervised exercise training in facilitating postoperative recovery in this patient population (41).
The large variations in the exercise programmes, in terms of moderate-to-high intensity ranging from 60% to 90% of heart rate maximum (HRmax), frequency ranging from twice a day to 3 times a week, and dura-tion from 5 min per exercise to a 60-min full session, influence the findings in the present review and limit the clinical applicability.
Differences in physical activity recommendations across the control groups may have influenced the effect sizes. Potential contamination of exercise in some of the control groups may have influenced, and most likely reduced, the effect of the relevant studies.
The present review did not clarify whether early initiation of exercise, within 2 weeks following lung resection, is more effective than exercise initiated later, which was hypothesized a priori. One study initiated exercise intervention within 2 weeks following surgery and therefore this analysis may not illustrate the true effect. Thus, the study contained a home-based non-supervised training programme following discharge, which potentially could have lowered adherence to the intervention, reducing its effect (32).
As a result it is not possible to evaluate whether early-initiated exercise training will improve the effect in exercise capacity and HRQoL.
The recruitment rates were low in 2 out of 6 studies (33, 35), potentially having caused a selected group of participants, e.g. the healthiest, the youngest and
Fig. 5. Forest plot: early or late initiated exercise interventions in exercise group vs control group (short term). SMD: standardized mean difference; 95% CI: 95% confidence interval.
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the fittest, to participate compared with those uninte-rested. Characteristics of the populations in the studies are therefore not necessarily consistent with a repre-sentative sample of patients with operable NSCLC. Information about eligible patients not interested in participating would be of great clinical interest with regard to applicability.
Quality of evidenceThe quality of evidence provided by the studies in-cluded in the analysis has been rated, according to GRADE, as low or very low, mainly because of some serious risks of bias, inconsistency in effect estimates and imprecision, as the small sample sizes caused wide confidence intervals. Consequently, the results must be interpreted with caution.
Strengths and limitations of the review processA strength of this review is the comprehensive lite-rature search by 2 review authors, which optimized sufficient identification of relevant studies, and suc-cessfully obtaining missing data.
In addition, the investigative work done to find ongo-ing, unpublished studies by searching trial registrations and contacting recognized authors in the research field improves the probability that all relevant studies were found. The number of studies excluded due to the langu-age criteria, however, probably limited the inclusion of further studies. The 3 studies excluded due to missing data also represent a limitation, as their effect estimates could have influenced the results of this review.
One of the excluded studies found that 6MWD improved by 35 m from preoperative baseline to post-intervention, the control group showed a decline by 59 m (p = 0.024) (38). Another study found no differences between the intervention group (homebased exercise plus 5 days with exercise in hospital) and the control group (36). What the 2 studies have in common is no post-operative baseline-outcomes to eliminate the impact of surgery; therefore it is difficult to compare the results with the results of this review.
The excluded study by Jacobsen et al. was a confe-rence article that did not report any results (37).
If the pooled data from the various instruments (VO2peak and 6MWD) used to assess exercise capacity did not measure the same outcomes, the results of the review may be biased. A recent study shows a diffe-rence in pulmonary oxygen when comparing 6MWD and the cardiopulmonary exercise test in patients with NSCLC following lung resection (17).
Studies on patients diagnosed with either chronic obstructive pulmonary disease or chronic heart failure, in contrast, found no differences in VO2peak obtained
using either the pulmonary oxygen uptake test or the 6MWD (42–44).
Including the most commonly used and recommen-ded questionnaires for measuring HRQoL in thoracic surgery patients could represent a strength as well as a limitation. The decision was made to maintain a high level of methodological quality, which is why the 3 questionnaires listed were considered useful for the population, though SF-36 has not been validated for patients with lung cancer. A limitation is the pooled data from the physical component domain of HRQoL, since it was assessed using instruments with different target groups, as one was a generic HRQoL questionn-aire (SF-36) and the other a cancer-specific HRQoL questionnaire (EORTC QLQ-C30).
The EORTC QLQ-C30 physical functioning do-main has shown a substantial convergent correlation with all of the 4 SF-36 physical summary component subdomains (r > 0.50) (45). The moderate similarity of the 2 instruments may have biased the result of the physical component of HRQoL, presenting the risk of an overestimate or underestimate of real effect.
The use of imported correlation coefficients in the calculation of SDs of mean differences in 2 of the in-cluded studies may have had an impact on the results. These SDs are estimates calculated based on changes found in previous studies with similar populations of patients with other cancer diagnoses (26). The SF-36 scores in that study were also reported to be similar to SF-36 scores for patients with chronic diseases, such as chronic obstructive pulmonary disease, hyperten-sion and congestive heart failure (26). This method of estimating the SDs could decrease the reliability of the reported results, due to an element of imprecision in the estimates (14). However, the estimated SD becomes a better replacement of the real SD compared with the use of an unpaired SD of the mean change.
Agreements and disagreements with other studies or reviewsA significant improvement in 6MWD was confirmed in a previous systematic review evaluating the effect of exercise interventions in patients with NSCLC fol-lowing lung resection (12). In contrast baseline outcome measures from pre- and post-surgery were included where the present review has all outcome measures conducted post-surgery to eliminate the impact of lung surgery and focus entirely on the effect of rehabilita-tion. In addition, the present review included 2 new RCTs with a total of 131 participants. Other previous systematic reviews confirmed that both pre- and post-operative exercise was associated with positive benefits on exercise capacity and some domains of HRQoL (6, 46). Different study designs were included in the pre-
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vious reviews, including a few RCTs, only one of which met the inclusion criteria of the current review (32).
During completion of the current review, a new review by Ni et al. (13) (evaluating the effects of pre- and post-operative exercise interventions) was published supporting our findings, in contrast their review included all study designs, as well as pre- and post-operative measurements.
The present review does not find that exercise improves the mental domain of HRQoL compared with usual care for patients having undergone lung resection; however, there might be a trend towards the direction of positive effects, but the confidence inter-vals indicate that these effects are very uncertain. The findings are in contrast to previous research in patients with COPD, patients with other cancer diseases and qualitative research in patients undergoing lung resec-tion for NSCLC (9). One of the possible reasons for this is how HRQoL was assessed, as SF-36 is a generic HRQoL questionnaire, or the lack of statistical power in the studies in the present review.
This review is the first to examine the effects of postoperative exercise training in patients with NSCLC following lung resection with inclusion of postopera-tive outcome measurements alone. This method does not include the involvement of the surgery on the out-comes. Inclusion of solely RCTs improves the quality of evidence. Moreover, this review is the first to focus on the effects of early-initiated exercise, although, due to lack of studies, this analysis did not lead to any conclusion regarding this question.
ConclusionThis review found that exercise may have beneficial ef-fects on exercise capacity and the physical component of HRQoL among patients following lung resection for NSCLC. However, since there are risks of bias, inconsistency and imprecision of findings, these results should be interpreted with caution.
Despite the overall low quality of the body of evidence, health professionals should consider refer-ring patients with NSCLC to an exercise programme following lung resection. Further research is needed to confirm the efficacy of exercise intervention in people with NSCLC, and whether these effects can be maintained beyond the active intervention period. Additional research is required to investigate when exercise intervention should be initiated following lung resection to obtain the best result and prevent or minimize postoperative impairments. This knowledge may contribute to the design of future exercise research in patients with operable NSCLC.
ACKNOWLEDGEMENTS This review is supported by grants from the Center for Integrated Rehabilitation of Cancer Patients (CIRE), which is supported by the Danish Cancer Society and the Novo Nordisk Foundation. Funding has also been provided by Rigshospitalet, University of Copenhagen; the Faculty of Health and Medical Sciences, University of Copenhagen; and the City of Copenhagen. Co-penRehab is supported by a grant from the City of Copenhagen.
The authors have no conflicts of interest to declare.
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