heavy resistance exercise in breast cancer survivors at risk for …2018.+heavy... · danish...
TRANSCRIPT
PhD Thesis
Heavy resistance exercise
in breast cancer survivors at risk for lymphedema
Kira Bloomquist
The University Hospitals Centre for Health Research (UCSF), University of Copenhagen, Rigshospitalet
Academic Supervisors
Lis Adamsen, Sandra C Hayes, Peter Oturai, Tom Møller, Bent Ejlertsen
Title Heavy resistance exercise in breast cancer survivors at risk for lymphedema
Author Kira Bloomquist, MHS, PT
Academic Supervisors Principal supervisor Lis Adamsen, Professor, RN, MSc.Soc., PhD University Hospitals Centre for Health Research (UCSF), Copenhagen University Hospital, Rigshospitalet, Copenhagen Ø, Denmark Department of Public Health, University of Copenhagen Primary co-supervisor, Sandra C Hayes, Professor, PhD Institute of Health and Biomedical Innovation, School of Public Health and Social Work, Queensland University of Technology, Brisbane, Australia Co-supervisor Peter Oturai, Chief Physician, MD, Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark Co-supervisor Tom Møller, Associate professor, RN, MPH, PhD University Hospitals Centre for Health Research (UCSF), Copenhagen University Hospital, Rigshospitalet, Copenhagen Ø, Denmark Co-Supervisor Bent Ejlertsen, Professor, MD, PhD Dept. of Oncology, The Finsen Centre and Danish Breast Cancer Group (DBCG), Copenhagen University Hospital, Rigshospitalet, Copenhagen Ø, Denmark
Financial Support The PhD has been supported by grants from the Center for Integrated Rehabilitation of Cancer Patients (CIRE), established by the Danish Cancer Society and The Novo Nordisk Foundation and the University Hospitals Centre for Health Research (UCSF), Copenhagen University Hospital, Rigshospitalet
Submitted January 2, 2018 PhD defense May 24, 2018 Assessment Committee Christoffer Johansen (chair), Professor, MD, Dept. of Oncology, The Finsen
Centre, Copenhagen University Hospital, Rigshospitalet and Danish Cancer Society
Jens Ahm Sørensen, Professor, MD, Head of research, Dept. of Plastic and Reconstructive Surgery, Odense Universitets Hospital, University of Southern Denmark
Anna Campbell, Associate professor in Clinical Exercise Science, Edinburgh Napier University
ISBN 978-87-90769-17-8
1
Table of content Table of content ................................................................................................................................................. 1
Acknowledgements ........................................................................................................................................... 4
List of manuscripts ............................................................................................................................................ 4
Abbreviations .................................................................................................................................................... 6
Summary............................................................................................................................................................ 7
Danish summary (Dansk resume’) .................................................................................................................. 10
Introduction ..................................................................................................................................................... 13
Background...................................................................................................................................................... 14
Breast cancer ............................................................................................................................................... 14
Ramifications of breast cancer-related lymphedema ................................................................................... 15
The lymphatic system and breast cancer ..................................................................................................... 15
Epidemiology of BCRL ............................................................................................................................... 16
BCRL diagnosis and clinical progression ................................................................................................... 17
BCRL treatment........................................................................................................................................... 18
Risk reduction recommendations and exercise............................................................................................ 19
Resistance exercise ...................................................................................................................................... 20
Heavy-load resistance exercise during adjuvant chemotherapy .................................................................. 20
Body & Cancer ............................................................................................................................................ 21
Aim .................................................................................................................................................................. 23
Material and methods ...................................................................................................................................... 24
Design .......................................................................................................................................................... 24
Study 1 ..................................................................................................................................................... 24
Study 2 ..................................................................................................................................................... 24
Study 3 ..................................................................................................................................................... 24
Participants .................................................................................................................................................. 26
Study 1 ..................................................................................................................................................... 26
Study 2 ..................................................................................................................................................... 26
Study 3 ..................................................................................................................................................... 28
Setting .......................................................................................................................................................... 29
Randomization and blinding ........................................................................................................................ 29
Study 2 ..................................................................................................................................................... 29
Study 3 ..................................................................................................................................................... 29
2
Interventions ................................................................................................................................................ 29
Study 2 ..................................................................................................................................................... 29
Study 3 ..................................................................................................................................................... 30
Measurement methods/outcomes ................................................................................................................ 31
Study 1 ..................................................................................................................................................... 31
Study 2 ..................................................................................................................................................... 32
Study 3 ..................................................................................................................................................... 33
Data analysis ................................................................................................................................................ 34
Study 1 ..................................................................................................................................................... 35
Study 2 ..................................................................................................................................................... 35
Study 3 ..................................................................................................................................................... 36
Ethical approval ........................................................................................................................................... 37
Study 1 ..................................................................................................................................................... 37
Study 2 ..................................................................................................................................................... 37
Study 3 ..................................................................................................................................................... 37
Results ............................................................................................................................................................. 37
Study 1 ......................................................................................................................................................... 37
Participants .............................................................................................................................................. 37
Body & Cancer participation ................................................................................................................... 38
BCRL point prevalence ........................................................................................................................... 38
BCRL vs. No BCRL ................................................................................................................................ 39
Study 2 ......................................................................................................................................................... 41
Participants .............................................................................................................................................. 41
Individual responses to resistance exercise ............................................................................................. 42
L-Dex ....................................................................................................................................................... 43
Inter-arm volume % difference ................................................................................................................ 43
BCRL symptoms ..................................................................................................................................... 43
Adverse events ......................................................................................................................................... 43
Study 3 ......................................................................................................................................................... 45
Participants .............................................................................................................................................. 45
Retention, adherence and adverse events ................................................................................................ 46
Lymphedema ........................................................................................................................................... 46
Upper extremity muscular strength ......................................................................................................... 49
Breast cancer-specific functional and symptom domains ....................................................................... 49
3
Discussion........................................................................................................................................................ 50
Lymphedema ............................................................................................................................................... 50
Point prevalence ...................................................................................................................................... 52
Muscular strength ........................................................................................................................................ 52
Methodological considerations .................................................................................................................... 53
Internal validity ....................................................................................................................................... 53
External validity ...................................................................................................................................... 56
Conclusion and clinical implications ............................................................................................................... 57
Perspectives and future research ...................................................................................................................... 58
References ....................................................................................................................................................... 60
Appendices ...................................................................................................................................................... 66
4
Acknowledgements I wish to express my sincere gratitude to everyone who contributed to the realization and completion of this thesis.
First and foremost, I would like to thank all of my supervisors. You all have brought experience and professional wisdom from
within your areas of expertise which have enriched my process and benefitted the thesis. To my principal supervisor Professor Lis
Adamsen, thank you for the opportunity to take on this work- without your support and belief in my abilities this thesis would not
have been realized. Enormous thanks goes to my primary co-supervisor Professor Sandi Hayes for the chance to come to Brisbane
and for excellent constructive supervision- I feel truly privileged to have worked with you. Further, special thanks goes to co-
supervisor Associate Professor Tom Møller for the opportunity to collect additional data in Study 3 and for support both
professionally and personally, and to Professor Bent Ejlertsen for coming on board with no hesitation- your clinical expertise and
knowledge of breast cancer treatment has been an asset alongside an incredibly pleasant demeanor. Finally, thanks to Chief Physician
Peter Oturai for many hours spent point-typing DXA scans, as well as providing constructive and timely feedback. Here I also want
to extend my gratitude to your staff for their willingness to collaborate and for excellent data collection.
I would also like to give tremendous thanks to Associate Professor, senior statistician Karl B. Christensen for statistical assistance in
all three studies. Thank you for your guidance in matters that I still only slightly understand. Further, thank you to Megan L. Steele
for your friendship and additional assistance in Study 2- equivalence, repeated measures over time, cross-over, GEE and interval
inclusion…. Need I say more?
I would also like to extend my gratitude to the breast cancer teams at the oncology departments of Rigshospitalet and Herlev hospital.
Thank you for your flexibility and willingness to adjust chemotherapy schedules so participants could partake in the studies. Further,
I would like to thank the breast cancer team at the Copenhagen Centre for Cancer and Health for help in recruitment of participants.
Clinical trials are only possible with the support of clinicians like you, who with an already busy work-load see the value in research
and make the time.
I also would like to express my deepest gratitude to the study participants who have dedicated their time and effort to this work.
Without your participation, these studies could not have carried out. Participating in research is an unselfish act as it does not
implicitly benefit you, the research subject, but rather future patients. Thank you for your contribution. You have made a difference.
I also would like to give my heartfelt thanks to all of my colleagues at UCSF (past and present), my “UCSF family”. Thank you for a
supportive and inspiring environment, for the laughter and for making UCSF a great place to come to work. Special thanks goes to
Christina Andersen for your unending support and for always taking the time for a chat, and Morten Quist for testing destiny and
your motto of “everything is possible”. Thanks to Julie Midtgaard for academic inspiration as well as girl-talk, and to fellow PhD-
student Eik Bjerre for your passion of methodology and high ethical standards. Also, thanks to the current Body and Cancer team:
Christian Lillelund for your contributions to the design and implementation of Studies 2 and 3 and for always making it fun to train,
and Birgit Nielsen for your stability and support in collecting data when I needed an extra hand, and to Jesper Børsen, my winter-
bathing friend, for filling in for me and ensuring that data was collected when I was gone. Thanks to Birgitte Nielsen for diligent data
collection and keying and assistance in Body and Cancer, and to Mikael Rørth for your support and advice based on your many years
of clinical research experience. Thanks to former office mates, Jakob Uth for your underplayed demeanor and fantastic sense of
humor and Karin Piil for setting the bar for how a Phd should be carried out. Thanks also to Mary Jarden, my fellow American for
“Denglish talk” and encouragement and to Jesper Frank Christensen for patiently trying to explain statistical matters as well as
assistance in the randomization of participants in Study 2. Further, thanks to research assistants Nicolas Kjerulf, Liza Wiedenbein,
Maria Petersen, Asker Kristensen, Marie Hagmann and Jonas Ravn for help in data collection and keying, as well as Maja Bohlbro
for also contributing to the preparation of data for analysis in Study 3. Thanks also to Kjeld Jensen for enduring support in practical
matters and last but not least, thanks to Bente Kronborg and Anders Larsen for always having an open door and providing friendly
and competent assistance. You have an enormous positive impact on the department and I thank you for that.
Finally I would like to thank all of my friends and family for support and for still being there despite my lack of engagement the last
couple of years. Special thanks goes to fellow PhD students Marie Collett and Britt Morthorst- it has been a gift to share the Phd ride
with you. Also thanks to my “Måge family”- I feel incredibly lucky to share daily life with you all, as well as my “Dragon boat
family” for your support and dedication to spreading the message of an active life during and after breast cancer. Also, an enormous
thanks goes to my parents Bente Nielsen and Gordon Bloomquist. Thank you for your love and support and for inspiring a sense of
social responsibility to try to make a difference. My deep felt gratitude also goes to Tim Barrett for assuring me that I was ok when I
doubted my own capabilities, and for supporting me in my journey from “Lille Mor” to “Dr. Mor”. Finally, to my daughter Aviaja,
thank you for an unwavering belief that I would successfully complete this thesis. May you possess the same unwavering belief in
yourself.
5
List of Manuscripts
This thesis is based on the following manuscripts:
Paper I
Bloomquist K, Karlsmark T, Christensen KB, Adamsen L. Heavy resistance training and
lymphedema: Prevalence of breast cancer-related lymphedema in participants of an exercise
intervention utilizing heavy load resistance training. Acta Oncol. 2014;53(2):215-25
Paper II
Bloomquist K, Hayes S, Adamsen L, Møller T, Christensen KB, Ejlertsen B, Oturai P. A
randomized cross-over trial to detect differences in arm volume after low- and heavy-load
resistance exercise among patients receiving adjuvant chemotherapy for breast cancer at risk for
arm lymphedema: study protocol. BMC Cancer. 2016;16:517
Paper III
Bloomquist K, Oturai P, Steele M, Adamsen L, Møller T, Christensen KB, Ejlertsen B, Hayes S.
Heavy-load lifting: Acute response in breast cancer survivors at risk for lymphedema. Med Sci
Sports Exerc. 2018; 50(2):187-95
Paper IV
Bloomquist K, Adamsen L, Hayes S, Lillelund C, Andersen C, Christensen KB, Oturai P, Ejlertsen
B, Tuxen MK, Møller T. Heavy-load resistance exercise in pre-diagnosis physically inactive
women at risk of breast cancer-related lymphedema during adjuvant chemotherapy: a randomized
trial. Manuscript prepared for submission to Acta Oncologica.
6
Abbreviations
ALND Axillary lymph node dissection
SLNB Sentinel lymph node biopsy
BCRL Breast cancer-related arm lymphedema
RH Rigshospitalet
HE Herlev Hospital
BIS Bioimpedance spectroscopy
DXA Dual-energy X-ray absorptiometry
EORTC QLQ-BR23 European Organization for Research and Treatment of Cancer quality of life
questionnaire breast-23
NRS Numeric rating scale
RM Repetition maximum
WHO World Health Organization
ICC Intraclass correlation coefficient
SE Standard error of the mean
SD Standard deviation
IQR Interquartile range
ITT Intention- to- treat
GEE Generalized estimating equation
CDT Complete decongestive therapy
7
Summary
Background
Despite a paucity of evidence, breast cancer survivors have historically been advised to refrain from
a number of activities including lifting heavy objects and resistance exercise in an effort to reduce
the risk of breast cancer-related lymphedema. However, clinical trials carried out over the last two
decades have consistently demonstrated that resistance exercise can be conducted without increased
risk of lymphedema. Nonetheless, as previous work utilized exercise prescription with low- to
moderate loads, uncertainty exists as to the upper-limits of resistance exercise loading, and breast
cancer survivors at risk for lymphedema continue to be encouraged to avoid heavy-lifting. Yet
exercise science literature indicates that a dose-response relationship exists between loads lifted and
gains in muscular strength and function, of potential benefit for breast cancer survivors receiving
chemotherapy. Therefore, the purpose of this thesis was to explore the safety of heavy-load
resistance exercise among women at risk of developing breast cancer-related lymphedema while
undergoing adjuvant chemotherapy.
Material and methods
Three studies were undertaken. Study 1 This was a cross-sectional trial including women treated
with chemotherapy for breast cancer (n = 149) who had participated in the Body & Cancer program
between January 2010 and December 2011. The Body & Cancer program is a six-week multimodal
exercise program including heavy-load resistance exercise. The primary outcome, self-reported
diagnosis of breast cancer-related lymphedema, was obtained from a structured telephone interview
carried out on average 14 months after participation in the exercise program. Study 2 This was a
randomized cross-over trial including women receiving adjuvant taxane-based chemotherapy for
breast cancer who had undergone axillary lymph node dissection (n =21). Participants were
randomly assigned to participate in a low- (two sets of 15–20 repetition maximum) and heavy-load
(three sets of 5–8 repetition maximum) upper extremity resistance exercise session first, with a one
week wash-out period between sessions. Swelling was determined by bioimpedance spectroscopy
(BIS) and dual energy x-ray absorptiometry (DXA), and breast cancer-related lymphedema
symptoms (heaviness, swelling, pain, tightness) were reported using a numeric rating scale (NRS)
(0-10). Outcomes were assessed immediately pre- and post-exercise, and 24- and 72-hours post-
exercise. Generalized estimating equations were used to evaluate changes over time between
groups, with equivalence between resistance exercise loads determined using the principle of
confidence interval inclusion. Study 3 This was a parallel group, randomized trial. Screened pre-
8
diagnosis physically inactive women receiving adjuvant chemotherapy for breast cancer (n=153)
participated in 12 weeks of 1) HIGH: supervised multimodal exercise including heavy-load
resistance exercise (85-90% 1 repetition maximum (RM), three sets of 5-8 repetitions) or 2) LOW:
walking supported by pedometer and one-on-one consultations. Outcomes were assessed at
baseline, 12 and 39 weeks and included: swelling (BIS, L-Dex scores; DXA, inter-arm volume %
difference; self-report, n( %)), lymphedema symptoms (NRS, 0-10), upper extremity strength (1
RM), and self-reported breast cancer specific function and symptoms (EORTC QLQ-BR23). Linear
mixed models with a heterogeneous autoregressive (1) covariance structure were used to evaluate
changes over time between groups. Equivalence was hypothesized for lymphedema outcomes, and
was determined using the principle of confidence interval inclusion.
Results
Study 1 On average, 14 months (range 4-26 months) post-participation in Body & Cancer, 27.5%
reported having been diagnosed with lymphedema by a clinician. When restricted to women with
axillary node dissection, 44.4% reported a clinician diagnosis of BCRL. No statistically significant
association between change in muscle strength during Body & Cancer and the development of
lymphedema was observed, nor was self-reported participation in resistance exercise with heavy
loads up to three months post-intervention. Study 2 The acute response to resistance exercise with
low and heavy loads was equivalent, with the exception of extracellular fluid at 72-hours post-
exercise with less swelling following heavy-loads. Study 3 Post-intervention equivalence between
groups was found for L-Dex and self-reported heaviness, tightness and swelling. Non-equivalence
was determined for inter-arm volume and pain, as deviations beyond equivalence margins indicated
reductions associated with participation in the HIGH intervention for these two outcomes. Further,
greater increases (p < 0.05) in upper extremity strength were seen in the HIGH group compared to
LOW at all assessments, and clinically relevant within group reductions in breast and arm
symptoms were observed in the HIGH group at 6 and 12 weeks.
Conclusion
The findings presented in this thesis indicate that breast cancer survivors at risk of breast cancer-
related lymphedema, can participate in and benefit from heavy-load resistance exercise while
receiving taxane-based chemotherapy, without an increased risk of exacerbating the development of
lymphedema.
9
Perspectives
Previous clinical trials using low to moderate resistance exercise loads have found gains in muscle
strength while mitigating adverse changes in physical components of quality of life, including
fatigue in this population, and it has been hypothesized that resistance exercise reduces taxane-
related edema. However, due to the dose-response relationship that exists between loads lifted and
gains in muscular strength and function it is feasible that superior benefits can be gained with
resistance exercise with heavier loads. Further it is plausible that participation in heavy-load
resistance exercise may instigate more effective lymphatic function than low-load resistance
exercise, and in doing so, potentially have a greater effect on reducing lymphedema risk. Therefore,
as this thesis indicates that resistance exercise safely can be performed with heavy loads, future
studies should carry out a head to head comparison between resistance exercise protocols to
establish optimal resistance exercise prescription for breast cancer survivors.
10
Danish summary (Dansk resume’)
Baggrund
Trods manglende evidens er brystkræftoverlevere blevet frarådet en række fysisk krævende
aktiviteter, bl.a. løft af tunge genstande og styrketræning, i et forsøg på at reducere risikoen for
brystkræftrelateret lymfødem. Igennem de sidste to årtier har kliniske forsøg imidlertid vist, at
styrketræning kan udføres uden øget risiko for lymfødem blandt kvinder diagnosticeret med
brystkæft. Der er dog fortsat uklarhed om de øvre grænser for vægtbelastningen ved styrketræning,
da tidligere forsøg har anvendt lav til moderat vægt i de gennemførte interventioner. Den
idrætsfysiologiske litteratur indikerer imidlertid, at der eksisterer et dosis-responsforhold mellem
vægtbelastninger og fremgang i forhold til muskelstyrke og –funktion, af potentiel positiv
betydning for brystkræftoverlevere, der modtager kemoterapi. Formålet med denne afhandling var
derfor at undersøge, hvor vidt det er sikkert at styrketræne med tung belastning for kvinder, der er i
risiko for at udvikle brystkræftrelateret lymfødem, under adjuverende kemoterapi.
Metode
Der blev gennemført tre studier. Studie 1 var et tværsnitsstudie, som inkluderede kvinder behandlet
for brystkræft med kemoterapi (n = 149), og som parallelt hertil deltog i Krop & Kræft i perioden
januar 2010 til december 2011. Krop & Kræft er et seks-ugers multimodalt træningsprogram, som
blandt andet indeholder tung styrketræning. Det primære effektmål var selvrapporteret
brystkræftrelateret lymfødem. Data blev indsamlet med et struktureret telefoninterview gennemført
i gennemsnit 14 måneder efter afsluttet deltagelse i Krop & Kræft. Studie 2 var et randomiseret
cross-over studie, som inkluderede kvinder med aksil-dissektion, der modtog adjuverende
taxanbaseret kemoterapi for brystkræft (n=21). Deltagerne blev tilfældigt allokeret til at deltage i en
styrketræningssession med lav (to sæt af 15-20 gentagelser) henholdsvis tung (tre sæt af 5-8
gentagelser) vægtbelastning, med en uges ”wash-out” periode mellem de to
styrketræningssessioner. Ekstracellulær væske i armene blev målt med bioimpedansspektroskopi
(BIS) og dual X-ray absorptiometri (DXA), og symptomer relateret til brystkræftrelateret lymfødem
(fornemmelse af stramhed, tyngde, hævelse, smerte) blev registreret med en numerisk rating skala
(NRS) (0-10). Målingerne blev foretaget umiddelbart før og efter styrketræningssessionerne samt
24 og 72 timer efter. Til at evaluere ændringer over tid mellem grupperne blev generalized
estimating equations anvendt. Ækvivalens mellem styrketræningssessionerne (lav / tung) blev
bestemt ved anvendelse af confidence interval inclusion. Studie 3 var et parallel-gruppe,
randomiseret forsøg. Kvinder, der inden deres brystkræft diagnose var defineret som fysisk inaktiv
11
(screenet) og som modtog adjuverende kemoterapi (n = 153) deltog 12 uger i: 1) HIGH:
Superviseret multimodalt træningsprogram med tung styrketræning (85-90% 1 repetitions
maksimum (RM), tre sæt 5-8 gentagelser) eller 2) LOW: Gangtræningsintervention med skridttæller
og face-to-face rådgivning. Data blev indsamlet ved baseline, samt efter 12 og 39 uger og
inkluderede: hævelse af armene (BIS, L-Dex-score; DXA, inter-arm volumen % forskel;
selvrapporteret hævelse, n (%)), lymfødem-symptomer (NRS, 0-10), muskelstyrke (1 RM) samt
selvrapporteret brystkræftspecifik funktion og symptomer (EORTC QLQ-BR23). Linear mixed
models med en heterogen autoregressiv (1) kovarians struktur blev anvendt til at evaluere ændringer
over tid mellem grupperne. Ækvivalens blev bestemt ved anvendelse af confidence interval
inclusion for effektmål relateret til lymfødem
.
Resultater
Studie 1 I gennemsnit 14 måneder efter deltagelse i Krop & Kræft (interval 4-26 måneder)
rapporterede 27,5% at de var blevet diagnosticeret med lymfødem (lymfødemterapeut eller læge).
Ved sub-analyse af kvinder med aksil-dissektion rapporterede 44,4% at være blevet diagnosticeret
med lymfødem. Der blev ikke observeret en statistisk signifikant association mellem ændring i
muskelstyrke og udvikling af lymfødem, hverken efter deltagelse i Krop & Kræft eller efter
selvrapporteret deltagelse i styrketræning med tung belastning op til tre måneder efter deltagelse.
Studie 2 Det akutte respons til styrketræning med lav og tung vægtbelastning var ækvivalent, med
undtagelse af ekstracellulær væske ved 72 timers opfølgning, som indikerede mindre væske efter
tung vægtbelastning. Studie 3 Post-intervention ækvivalens mellem grupper blev fundet for L-Dex
og selvrapporterede symptomer (tyngde, stramhed og hævelse). For inter-arm volumen og smerte
kunne ækvivalens ikke demonstreres, men indikerede større reduktioner associeret til deltagelse i
HIGH interventionen sammenlignet med LOW for disse to effektmål. Analyser af muskelstyrke
viste, at HIGH gruppen øgede muskelstyrken i overekstremiteterne (p <0,05) sammenlignet med
LOW. Desuden blev bryst- og arm-symptomer reduceret ved 6 og 12 uger i HIGH gruppen, uden
signifikant forskel mellem grupperne.
Konklusion
Resultaterne fra denne afhandling indikerer, at kvinder med brystkræft i risiko for at udvikle
brystkræftrelateret lymfødem kan deltage i og profitere af tung styrketræning under behandling med
taxanbaseret kemoterapi uden øget risiko for udvikling af lymfødem.
12
Perspektivering
Set i lyset af det dosis-responsforhold der eksisterer mellem belastning og fremgang i muskelstyrke
og -funktion, kan der antageligvis opnås større fordele ved styrketræning med tungere vægte. Det er
ligeledes plausibelt at deltagelse i styrketræning med tung belastning potentielt kan medføre en
mere effektiv lymfatisk funktion end styrketræning med lav belastning og dermed have en positiv
effekt på risikoen for at udvikle lymfødem. Da denne afhandling indikerer, at styrketræning med
tung belastning er sikker at udføre, bør fremtidige undersøgelser derfor sammenligne
styrketræningsprotokoller for at klarlægge den optimale styrketræningsdosering for
brystkræftoverlevere i risiko for at udvikle lymfødem.
13
Introduction
Breast cancer-related lymphedema (BCRL) is a feared adverse effect of breast cancer treatment (2,
3) affecting approximately one in five breast cancer survivors (4). At present, though evidence
suggests a predisposition for developing BCRL (5, 6) ability to accurately predict who will develop
BCRL is limited.
Historically, breast cancer survivors have been advised to refrain from a number of activities
including lifting heavy objects and resistance exercise in an effort to avoid the development of
BCRL (7-9). These recommendations were based on anecdotal concerns, that heavy-lifting would
increase lymph production, which would then overload an impaired lymph system and thus trigger
the development of BCRL (9).
During the last two decades, numerous studies have evaluated and consistently demonstrated that
resistance exercise is beneficial to strength and outcomes of importance for quality of life, and can
be conducted without increased risk of BCRL after treatment for breast cancer (7, 8, 10, 11).
However, as previous work utilized exercise prescription with low- to moderate loads, breast cancer
survivors continue to be encouraged to avoid heavy-lifting. Further, there is a paucity of evidence
confirming upper-limits of resistance exercise loading for women at risk of BCRL.
At present, two prospective studies have evaluated the safety of resistance exercise with heavy
loads in women with clinically stable BCRL who had been diagnosed with breast cancer at least a
year before study inclusion (12, 13). Both studies found that the extent of arm swelling and
associated BCRL symptoms remained stable immediately post-, 24- and 72-hours after one bout of
resistance exercise (12), and after twelve-weeks of regular resistance exercise, irrespective of
whether low- or heavy-loads were lifted (13). While these findings provide meaningful information
for breast cancer survivors with BCRL who have completed chemotherapy and radiotherapy, they
cannot be generalized to the at-risk population undergoing chemotherapy.
This thesis focuses therefore on the safety of resistance exercise with heavy loads during adjuvant
chemotherapy in breast cancer survivors at risk for lymphedema.
14
Background
Breast cancer
Breast cancer is the second most common cancer in the world after lung cancer, and is the most
frequent cancer among women with an estimated 1.67 million new cases diagnosed in 2012,
representing 25% of all cancers in women (14). In 2015, 4,767 women were diagnosed with breast
cancer in Denmark, corresponding to 24.8% of all cancers. Comparatively, just 38 men were
diagnosed with breast cancer in the same period (15). Survival rates vary worldwide, but in general
rates have improved especially in countries where breast cancer is detected early and there is access
to improved treatment strategies (14). Treatment modalities for breast cancer include surgery,
chemotherapy, radiotherapy as well as targeted and hormonal therapy, with subtype and stage of
breast cancer determining treatment strategy (16). While these treatment modalities are increasingly
effective in terms of survival, they are also associated with a range of treatment specific adverse
acute and late side effects including fatigue, pain and lymphedema that negatively impact the
quality of life of breast cancer survivors (17-19). In Denmark, breast cancer prevalence has
increased over the past decades (Figure 1) and five year survival rates from 2014 were estimated at
86% (1). As such, with more people surviving breast cancer, adverse late effects, are a growing
public health concern.
Figure 1. Age-standardized breast cancer prevalence in men and women in Denmark (1990-2014)
Adapted from the NORDCAN database, ancr.nu (1).
15
Ramifications of breast cancer-related lymphedema
BCRL is initially characterized by accumulation of excess protein-rich extracellular fluid resulting
in regional swelling of the hand, arm, breast or torso on the surgical side as a consequence of
disruption or damage to the axillary lymphatic system due to breast cancer treatment (9, 20-23).
This incurable condition is negatively associated with significant physical, functional, social and
psychological burden (24-27) impacting daily living, work and quality of life (24, 28-30). BCRL
and efforts to reduce the risk of BCRL impose limitations on the lives of breast cancer survivors,
with some women reporting more distress related to the threat of BCRL than with breast cancer
itself (3). BCRL is a persistent reminder of breast cancer and the physical and functional
manifestations include decreased mobility, skin changes and visible swelling as well as sensory
disturbances, discomfort and pain (3, 22). Considerable psychosocial effects are also associated
with BCRL including negative perceptions of self-image, appearance and sexuality (25, 26).
Further, breast cancer survivors with lymphedema are faced with extra financial burden due to the
cost of lymphedema treatment (31) as well as the economic ramifications of reducing work hours,
changing work places or exiting the workforce which can be a necessity especially for those with
more severe lymphedema (25, 28, 32).
The lymphatic system and breast cancer
The lymphatics are a one-way transport system that carries fluid and plasma proteins that have
leaked from tissues into the interstitial space, back into the cardiovascular system (33). The
lymphatic system supports the cardiovascular and immune systems and has three major functions
including maintenance of fluid balance (homeostasis), fat absorption by the intestinal lymphatics,
and immunological defense (21). The lymphatic system aids in the removal of excess fat, water,
cellular debris and foreign material from body tissues, as well as larger proteins by way of lymph
fluid transport. Lymph fluid is derived from interstitial fluid upon entry into lymph capillaries that
are found near the arteriovenous anastomoses that serve all systemic tissues (9, 21). Formation and
propulsion of lymph through lymphatic vessels is primarily dependent on extrinsic mechanisms
such as skeletal muscle contraction (muscle pump) and pressure changes due to respiration and
arterial pressure pulsations (33). However, once lymph fluid moves beyond the lymphatic
capillaries, movement of lymph is dependent on contraction of smooth muscle that line the
contractile lymphatic vessels driven by pacemaker cells as well as one-way valves that help prevent
backflow (lymphatic pump) (21, 33). The lymphatic system is comprised of a superficial layer
(drainage for skin and subcutaneous tissues) and a deep layer (drainage for e.g. muscles, joints and
16
bones) that drain into site specific lymph nodes that filter foreign particles, process antigens and
produce appropriate immune response (5). As such, bacteria, proteins and other materials from a
specific body part are delivered to a specific lymph node that serves that tissue. Consequently, if
lymph nodes are damaged or removed, the immune response is interrupted as well as the ability to
remove excess fluid from the tissue supported by the specific lymph node and explains, in part,
potential ensuing edema of that region (9, 21).
The lymphatic vessels that transport lymph from the breast to the axillary lymph
nodes are the preferential route for the metastatic spread of breast cancer, with status of the axillary
lymph nodes a determinant of breast cancer staging and subsequent treatment (6, 21, 34). The
sentinel node (or nodes) is typically the first lymph node to which cancer cells spread from
a primary tumor, and histopathological examination by means of a sentinel lymph node biopsy
(SLNB) determines whether cancer cells are present. A negative SLNB suggests that cancer has not
spread to nearby lymph nodes and no further surgery is warranted. However, in Denmark if the
biopsy contains macrometastasis or micrometastasis/isolated tumorcells in 3 or more sentinel nodes,
subsequent removal of the axillary lymph nodes, usually levels 1 and 2, known as axillary lymph
node dissection (ALND) is performed (35). Consequently, as more lymph nodes are removed,
compared to SLNB, ALND is associated with considerably more morbidity and an increased risk of
developing BCRL(4). However, not all breast cancer survivors with ALND develop lymphedema,
and cases of grade 1or higher lymphedema are seen in breast cancer survivors with only SLNB,
irrespective of axillary radiotherapy. At present, though a predisposition for BCRL likely exists, the
complex pathophysiology of BCRL remains unclear rendering limited ability to predict who will
develop this condition (6, 21).
Epidemiology of BCRL
The incidence of BCRL is difficult to quantify
with factors such as type of study design, time
since- and type of breast cancer treatment and
method of lymphedema assessment affecting
incidence rates (4). In Denmark, an incidence of
860 to 1260 new cases per year has been
estimated (31) and a nationwide study by
Gartner et al. (36) found point prevalence of self-
reported BCRL symptoms corresponding to 37%
17
in 2008 and 31% in 2012, in women who had received treatment for unilateral breast cancer in 2005
and 2006. To date, the best estimate of BCRL incidence is based on a systematic review and meta-
analysis by Disipio et al., 2013, which found a cumulative incidence rate of 16.6% (95% CI 13.6 –
20.2), based on data from 72 studies (4). However, when restricted to 30 prospective cohort studies,
the incidence estimate was 21.4% (14.9- 29.8). In breast cancer survivors with ALND, incident
BCRL (18 studies) was approximately four times higher (19.9%, 13.5 – 28.2) as compared to SLNB
(5.6%, 6-1 – 7.9%). Though risk of BCRL is lifelong, incident BCRL increased up to two years
post- surgery (18.9%, 14.2 - 24.7) based on 24 studies, after which time, incidence decreased (15.6
%, 10.0 – 23.5). This is in line with findings from a prospective study by Norman et al. (37) that
showed 80% of the women that developed BCRL, did so within 2 years post-surgery.
Findings from the aforementioned systematic review by Disipio and colleagues also
collated risk factor findings from 29 studies and found that there was ‘strong’ evidence
demonstrating the following characteristics increased risk of lymphedema: ALND / greater number
of lymph nodes removed, more extensive breast surgery and higher body mass index (BMI) ≥ 25.
Further, there was ‘moderate’ evidence suggesting that higher number of metastatic nodes, anti-
cancer treatment with chemotherapy and radiotherapy as well as physical inactivity also increased
risk of BCRL (4).
BCRL diagnosis and clinical progression
Though classification criteria for defining and grading BCRL severity have been developed
including a staging system by the International Society of Lymphology and Common Toxicity
Criteria from the National Cancer Institute (Table 1) (20, 22, 38), no universal definition of BCRL
exists. Further, no gold standard assessment of BCRL exists as current measurement methods
including circumferential measurements, self-report of symptoms, water displacement, perometry
and bioimpedance spectroscopy have advantages and disadvantages, as well as varying diagnostic
thresholds applied (4, 39). The inability to identify a gold standard definition and measure of
lymphedema is in part due to several challenges inherent to BCRL presentation. First, many breast
cancer survivors experience transient swelling related to surgery and taxane-based chemotherapy in
the first year after surgery that resolves by itself (40). However, as there is no accepted time line for
defining transient versus chronic lymphedema, some transient cases are mistakenly diagnosed as
chronic. Importantly, though, transient swelling during the first year after surgery has been
identified as a strong predictor of chronic BCRL at 18 months, why prospective monitoring of these
patients is warranted (41). Further, the distribution of swelling can vary from person to person.
18
Swelling may for example be confined to a specific region such as the hand in some, while in others
swelling is restricted to the forearm or upper arm (5). Additionally, early BCRL is characterized by
a latent phase whereby an accumulation of excess extracellular fluid is present, but where no visible
swelling is detected. As BCRL progresses this then manifests as visible swelling (22), and then in
later stages the excess extracellular fluid initially characterizing BCRL is replaced with fibrotic and
adipose tissue (21). Therefore, it has been proposed that the use of multiple measures, incorporating
both objective and subjective measures may be the most comprehensive way to capture BCRL cases
and to monitor BCRL over time (4, 39).
ISL staging CTC v3.0 grading
0 Latent or subclinical LE
No evidence of swelling
Exists prior to overt edema
Normal
1 Pitting
Elevation of limb reduces swelling
<20% increase in limb volume
5%-10% inter-limb discrepancy in volume or circumference at point of greatest
visible difference; swelling or obscuration of anatomical architecture on close
inspection: pitting edema
2 Elevation of limb does not reduce
swelling
Pitting is present in early Stage II due
to tissue fibrosis
20% to 40% increase in limb volume
>10%-30% inter-limb discrepancy in volume or circumference at point of greatest
visible difference; readily apparent obscuration of anatomical architecture;
obliteration of skin folds; readily apparent deviation from normal anatomical
contour
3 Lymphostatic elephantiasis
Pitting is absent
Trophic skin changes present
>40% increase in limb volume
>30% inter-limb discrepancy in volume; lymphorrhea; gross deviation from normal
anatomical architecture; interfering with activities of daily living
4 Progression to malignancy (e.g., lymphangiosarcoma); amputation indicated;
disabling
BCRL treatment
The majority of BCRL is mild (20, 37) and the aim of treatment is to contain swelling and alleviate
symptoms. The current standard of treatment for BCRL “complete decongestive therapy” (CDT) is
comprised of multiple elements including a massage technique called manual lymph drainage,
compression (bandaging or garments) of the affected area, remedial exercises, skin care and
education in self-care (31, 38, 42). CDT is delivered by specially trained lymphedema therapists
and involves two phases. The aim of the first phase is to reduce the extent of swelling. This
intensive and time consuming phase can last up to four weeks and involves frequent therapist-
Table 1. Lymphedema staging and grading criteria: International Society of Lymphology (ISL) and
National Cancer Institute Common Toxicity Criteria version 3 (CTC v3.0)
19
delivered treatment sessions including bandaging of the affected body part. After reaching a plateau
in the extent of swelling, home-based maintenance (phase two) then begins to retain the effects of
the intensive phase. Depending on the severity of the lymphedema this entails wearing a custom-
fitted compression garment during the day, performing remedial exercises, wearing special night
garments and using pneumatic compression devices (22). Though CDT involves two phases and
contains these various components, the treatment delivered is based on the clinical presentation
and could, for example, include only compression or manual lymph drainage. Other less common
treatment strategies include pharmacological and surgical approaches such as liposuction, lymph
node transplants, lymph-venous anastomosis (22, 23, 42), while the potential of stem cell surgery is
being explored (43). The treatment of lymphedema will not be addressed further in the present
thesis.
Risk reduction recommendations and exercise
Because uncertainty exists as to why some develop BCRL and others do not, and because
prevention of BCRL is preferable to the mitigation of BCRL symptoms, breast cancer survivors are
encouraged to adopt a range of precautionary behaviors in an effort to reduce the risk of BCRL (22,
44). The risk reduction guidelines or strategies are intended to minimize lymphatic overload of the
at-risk extremity, and are based in large part on pathophysiological principals and expert opinion
rather than scientific evidence (42, 45). These recommendations include avoiding constriction of the
at-risk arm (including blood pressure cuffs), extreme temperatures (e.g. sauna) and trauma or injury
and blood draws on the at-risk extremity (44, 45). Historically avoidance of vigorous, repetitive
upper-body activities was also recommended as well as avoidance of heavy lifting, often with
restrictions of not lifting more than 2-7 kilograms (9). As a consequence, daily living activities were
restricted (vacuuming, child care, grocery shopping) along with upper-body, recreational activities
including resistance exercise (9). However, a growing body of evidence has emerged over the last
two decades, with studies consistently finding participating in resistance exercise to be a safe and
effective exercise modality in breast cancer survivors at risk for lymphedema (7, 8, 10, 11).
Nonetheless, as exercise prescription of previous work has been limited to loads considered to be
low to moderately heavy, questions remain as to the safety of resistance exercise with heavy loads
and lymphedema risk (7). Additionally, uncertainty still exists as to whether intermittent heavy-
lifting in activities of daily living need be avoided (2, 46).
20
Resistance exercise
Skeletal muscle has the ability to alter its phenotypic profile in response to specific stimuli with
aerobic and resistance exercise representing two exercise modalities with distinct ability to modify
skeletal muscle (47). Specifically, resistance exercise is characterized by short periods of high
contractile muscle performance against external load and is considered the optimal exercise
modality to increase muscle mass and strength (48-50).
The extent of strength enhancement is dependent on a number of exercise prescription
variables including the magnitude of loads lifted. The term repetition maximum (RM) is used to
describe resistance exercise prescription, with RM corresponding to the maximal amount of weight
lifted for a number of exercise movements. Thus, a 1 RM is the heaviest weight that can be lifted
once and only once, corresponding to maximal strength or 100% RM (51). As such, an 8 RM is the
heaviest weight that can be lifted only eight times. To induce desirable adaptations in muscle mass
and strength the American College of Sports Medicine recommends that resistance exercise should
be carried out at a minimum intensity corresponding to 60% 1 RM. Importantly, a dose-response
relationship exists in regard to loads lifted and gains in muscle strength outcomes, with loads of 80-
100% 1 RM or higher being recommended for continued, long-term progression in muscle strength
(48, 50). Additionally, beyond skeletal muscle adaptations, resistance exercise with heavy loads has
also been identified as an osteogenic exercise modality due to the adaptive nature of bone that
requires heavier loads (52).
Heavy-load resistance exercise during adjuvant chemotherapy
There are several reasons why resistance exercise with heavy loads is relevant during adjuvant
chemotherapy for breast cancer. First, participation in resistance exercise with low to moderate
loads (60-80% of 1 repetition maximum (RM) for 8-15 RM) has been found to reduce or mitigate
chemotherapy-related fatigue (53, 54) with evidence to suggest that a dose-response relationship
exists between increasing loads lifted and reductions of fatigue (53). Further, reductions in physical
activity contributing to weight gain, characterized as sarcopenic obesity, is common during adjuvant
chemotherapy for breast cancer (55-57). Sarcopenic obesity is defined as no change or decline in
muscle mass in the presence of increased body fat) (55), and is adversely associated with reductions
in muscle strength and functional impairment (49, 58). As such, resistance exercise represents an
important countermeasure (8, 54, 59) and is recognized as an effective modality to control or revert
sarcopenia, thereby contributing to improved functional levels and overall health (48, 49).
21
Nonetheless, though increases in muscle strength and reductions in fatigue have been
observed with resistance exercise-prescription using lower loads, it is feasible that resistance
exercise with heavy loads, could yield superior reductions in fatigue and increases in muscle
strength. In turn, this could positively influence functional aspects of quality of life in this
population. Also, in Denmark, standard adjuvant chemotherapy for breast cancer consists of
combination taxane-based chemotherapy (16) with generalized swelling characterized by an
increased level of the interstitial component of extracellular fluid as a known side-effect (40, 60).
For some breast cancer survivors this may manifest as transient arm swelling and for others as
chronic lymphedema. It has been hypothesized that resistance exercise, through the effects of the
muscle pump, could mitigate the extent of arm swelling (33, 40). At present, no studies evaluating
the effect of resistance exercise and BCRL have explicitly included participants undergoing taxane-
based chemotherapy why uncertainty remains as to the impact of resistance exercise and resistance
exercise load on taxane-based swelling. This is especially relevant as the majority of individuals
who receive chemotherapy for breast cancer, receive taxane-based chemotherapy. Therefore, in
light of the potential for superior benefits, the safety of resistance exercise with heavy loads in
regard to BCRL development during taxane-based chemotherapy should be established.
Body & Cancer
Against this back-drop, the author of this thesis has been affiliated with the Body & Cancer
program since 2003. This program started in 2001 as a randomized controlled trial designed to
compare the effectiveness of a multimodal exercise intervention to a wait-list control group on rate
of cancer-related fatigue (61). Since 2007 Body & Cancer has been offered as an adjunct to
chemotherapy in the Copenhagen area, and is today offered at seven hospitals throughout Denmark.
To date, approximately 1800 participants representing over 21 diagnoses have participated in Body
& Cancer in the Copenhagen area alone, with approximately half receiving chemotherapy for breast
cancer.
The Body & Cancer program is a six-week, nine-hour weekly, group based (10-15
participants), multimodal exercise intervention comprised of both low-intensity components
(relaxation techniques, body awareness training and Swedish massage) and high-intensity
components (aerobic-and resistance exercise). Prior to each high intensity exercise session,
participants are screened (e.g. musculoskeletal issues, temperature, blood pressure) to ensure safety
of participation.
22
In Copenhagen, exercise sessions are held at training facilities affiliated with the Copenhagen
University Hospital, Rigshospitalet and supervised by a cancer nurse specialist and physical
therapist. Of particular interest for this thesis is the high intensity component which consisted of an
aerobic-based warm-up followed by heavy-load resistance exercise followed by 15-30 minutes of
interval aerobic exercise on a stationary bike with peak loads of 85-95% of each participant’s
maximal heart rate. The resistance exercise program comprises of six machine-based exercises
(Technogym®, Gamettola, Italy), each targeting major muscle groups of the body including the
upper-extremities (chest press, latissimus pull down, abdominal crunch, back extension, leg press
and knee extension). Resistance exercise loads are based on a 1 RM strength test for each exercise.
During the first week participants are instructed to lift loads corresponding to 2-3 sets of 8-12
repetitions at 70% 1 RM, progressing to 80% 1 RM in week two. From week three forward, loads
lifted correspond to 3 sets of 5-8 repetitions at 80-90% 1 RM. Participants who develop signs of
BCRL (e.g. sensations of heaviness, visual swelling) or experience exacerbations of an existing
BCRL are instructed to reduce loads or refrain from exercises of the upper extremities and are
referred to a lymphedema therapist for evaluation and treatment. No data has previously been
collected regarding BCRL in this cohort.
Monday Tuesday Wednesday Thursday Friday
Aerobic and resistance
exercise (1.5 h) Body awareness (1.5 h)
Relaxation (.5 h)
Aerobic and resistance
exercise (2 h)
Aerobic and resistance
exercise (1.5 h)
Relaxation training (.5 h) Relaxation training (.5 h)
Relaxation training (.5 h)
Massage (.5 h) Massage (.5 h)
Table 2. Body & Cancer overview
23
Aim
In light of the uncertainty surrounding heavy-load lifting in breast cancer survivors at risk for
BCRL, the overall aim of this thesis was to explore the safety of heavy-load resistance exercise
among women at risk of developing BCRL while undergoing adjuvant chemotherapy. To meet this
aim, three studies were undertaken.
The specific aims of the three studies comprising this thesis were:
Study 1 To determine the prevalence of BCRL in breast cancer survivors who had participated
in a six-week multimodal exercise intervention including heavy-load resistance
exercise concomitant to receiving chemotherapy (Body & Cancer). Further, this study
explored associations between engaging in resistance exercise with heavy-loads and
the development of BCRL.
Study 2 To assess the initial lymphatic response to resistance exercise with low-compared to
heavy-load resistance exercise in breast cancer survivors at risk of BCRL, by
comparing acute changes in extracellular fluid, arm volume and BCRL symptoms
after a session of low- and heavy-load resistance exercise in women who had
undergone axillary lymph node dissection and were receiving taxane-based adjuvant
chemotherapy.
Study 3 To prospectively evaluate the effect of a supervised, multimodal intervention
including heavy-load resistance exercise compared with a home-based walking
intervention on BCRL outcomes, muscle strength and breast cancer-specific quality of
life domains in pre-diagnosis physically inactive breast cancer survivors during
adjuvant chemotherapy.
24
Material and methods
Each of the three studies was conducted separately with the objective of addressing its specific
research aim. The data collected within each study are not combined, but are summarized to form a
comprehensive whole in the discussion and conclusion sections. Table 3 gives an overview of the
included studies.
Design
Study 1
This PhD was pragmatically formed beginning with a cross-sectional study to determine prevalence
of BCRL and associations with treatment related risk factors and heavy-load resistance exercise,
among former participants of Body & Cancer. While causality cannot be established with this study
design, findings from Study 1was hypothesis generating and provided the platform for the
subsequent studies.
Study 2
Study 2 utilized a randomized, cross-over design to determine the acute lymphatic response to
low- and heavy-load resistance exercise. As between-person variations are inherently eliminated,
this design lends more statistical power with the practical advantage of a smaller sample size,
providing the basis for an efficient comparison between the two resistance exercise loads (62).
While results from this type of study can provide important preliminary information, specifically
about the acute lymphatic response, a longitudinal study is required to determine the longer term
effects of repeated exposure to heavy-load resistance exercise.
Study 3
Study 3 was conducted within the framework of an existing parallel group, randomized trial. The
study evaluated the effect of a multimodal exercise intervention including heavy-load resistance
exercise vs. a walking intervention supported by a pedometer and counselling, with aerobic capacity
as the primary outcome. Therefore, BCRL results are based on secondary outcomes in this trial.
25
Study / Paper 1 / I 2 / II & III 3 / IV
Hypothesis Participation in an exercise
intervention utilizing heavy-load resistance exercise would not be
associated with incidence BCRL.
Response would be similar between resistance
exercise loads for all outcomes.
Superior muscular strength and
breast cancer-specific domains after HIGH compared to LOW. BCRL
outcomes will be similar irrespective
of intervention.
Design Cross-sectional study Randomized cross-over trial Parallel-group randomized trial
Participants (n = 149) (n = 21) (n = 153)
Sample Breast cancer survivors who had participated in Body & Cancer during
chemotherapy
Excluded:
BCRL diagnosis prior to Body
&Cancer
Recurrent disease and mortality at study initiation
Women receiving standard adjuvant chemotherapy for stage I-III breast cancer with
no pre-existing cancer diagnosis
Over 18 years of age
Unilateral breast surgery and axillary node
dissection
Excluded: Existing BCRL
Conditions limiting resistance exercise of the
upper extremities Regular heavy resistance exercise (>1 / week)
during the last month
Self-reported physically inactive women receiving adjuvant
chemotherapy for stage I-III breast
cancer.
WHO performance status 0-1
Excluded:
Symptomatic heart disease and/or pathological echocardiogram
Diagnosed acute coronary syndrome
within 6 months Contraindication to exercise
Unable to read or understand
Danish.
Randomized
concealed allocation
Not applicable Yes Yes
Interventions Not applicable One session of low- load resistance exercise One session of heavy-load resistance exercise
HIGH: 12-week supervised, group-based intervention including heavy-
load resistance exercise
OR LOW: 12-week home-based
individual walking intervention to
support physical activity
Measurement
methods
Telephone questionnaire
Medical records
Body & Cancer database
BIS
DXA
NRS
BIS
DXA
NRS Structured interview
1 RM
EORTC QLQ-BR23
Outcomes Self-reported clinically diagnosed
BCRL
Primary: Arm extracellular fluid
Secondary: Inter-arm volume
BCRL symptoms
Arm extracellular fluid
Inter-arm volume
BCRL symptoms Self-reported swelling
Muscle strength
Functional & symptom domains
Blinded Not applicable Data collection & analyses Data collection & analyses
Analysis Prevalence / Associations Equivalence Superiority / Equivalence
Statistics Point prevalence
X2-test Fisher’s exact test
General estimating equation
Confidence interval inclusion
Linear mixed model: heterogeneous
autoregressive (1) covariance Confidence interval inclusion
Table 3. Material and methods overview of the three studies comprising this thesis
Abbreviations: BCRL breast cancer-related lymphedema, WHO World Health Organization, BIS Bioimpedance spectroscopy, DXA Dual X-
ray absorptiometry, NRS Numeric rating scale, RM repetition maximum, EORTC QLQ-BR23 European Organization for Research and
Treatment of Cancer quality of life questionnaire breast-23
26
Participants
Study 1
Breast cancer patients who had participated in Body & Cancer between January 2010 and
December 2011 were identified from the Body & Cancer database (n=149). Participants were
eligible for Body & Cancer if they were receiving chemotherapy for cancer at a university hospital
in the Copenhagen area, had a World Health Organization (WHO) performance status of 0-1, and
otherwise had been approved to participate by the treating oncologist. Potential participants for the
cross-sectional analysis were screened for BCRL, recurrent cancer and mortality status in medical
records and excluded if identified. Figure 2 details the recruitment and exclusion process.
Study 2
A convenience sample of women (n =21) receiving adjuvant taxane-based chemotherapy for stage
I-III breast cancer who had undergone ALND, were recruited from the Copenhagen Centre for
Cancer and Health and from a waitlist to participate in Body & Cancer between March 2015 and
December 2016. Potential participants were screened for eligibility (over 18 years of age, unilateral
Figure 2. Flowchart over participants in Study 1
27
breast surgery, first diagnosis of breast cancer) and excluded if they had a known clinical diagnosis
of BCRL and/or had conditions limiting resistance exercise of the upper extremities, or had
participated in regular (>1 × / week) upper extremity heavy resistance exercise during the last
month. Those meeting eligibility were then assessed for BCRL after the third cycle of
chemotherapy. Those with evidence of lymphedema (L-Dex >10 assessed using bioimpedance
spectroscopy (BIS) or visual inspection (CTC v3.0) were excluded from participating in the study
and referred to a lymphedema therapist for evaluation and treatment (Figure 3).
Figure 3. Flowchart over participants in Study 2
28
Study 3
Participants (n =154) were recruited between January 2014 and July 2016 at the oncology
departments of The Copenhagen University Hospital, Rigshospitalet (RH) and Herlev Hospital
(HE). Women were screened/interviewed for eligibility by nurses / physicians upon initiation of
adjuvant chemotherapy for stage I-III breast cancer. Eligibility criteria included a WHO
performance status of 0-1 and physical activity levels retrospectively rated as less than 150 minutes
of regular, moderate- intensity and / or less than 2 x 20 minutes of high-intensity exercise per week
(Danish national recommendations (63)), three months prior to diagnosis. Eligible participants were
then referred to the research team and matched against exclusion criteria (diagnosed acute coronary
heart syndrome within the past six months, symptomatic heart disease, pathological
echocardiogram, contraindication for exercise noted in medical records, unable to read or
understand Danish) (Figure 4).
Figure 4. Flow chart over participants in Study 3
29
Setting
The three studies have been carried out at exercise facilities located at the University Hospitals
Centre for Health Research, University of Copenhagen, Rigshospitalet.
Randomization and blinding
Inherent to exercise studies, participants, nurses and physical therapists delivering the interventions
in Study 2 and 3 were aware of group allocation.
Study 2
Resistance exercise order (low- or heavy-load first) for the experimental sessions was randomly
allocated using a computer-generated random sequence (1:1 ratio). Blinded data collection was
performed by medical technicians at the Department of Clinical Physiology and Nuclear Medicine,
at the Copenhagen University Hospital, Rigshospitalet. Further all DXA scan analyses were
performed blinded to intervention order. Subsequently, data was keyed by research assistants, and
statistical analyses were performed with no knowledge of allocation by an external statistician.
Study 3
Following baseline assessment, participants were sequentially numbered and stratified by age
(<48/48+ years) and hospital (RH/HE). Intervention allocation (1:1) was determined by a
computerized, random number generated at the Copenhagen Trial Unit, an external clinical research
unit. All data collection and subsequent data entry were performed blinded to group allocation by
study staff. Further, all statistical analyses were performed blinded to group allocation by a senior
statistician at the University of Copenhagen.
Interventions
Participants were encouraged to contact study personnel if signs or symptoms of BCRL developed
(Studies 2 and 3) or exacerbation of an existing BCRL (Study 3) occurred during the study period,
and were referred to a lymphedema therapist for evaluation and treatment. The type and duration of
treatment delivered by the therapist was not recorded.
Study 2
Participants completed two familiarization sessions, followed by two experimental sessions (one
low- and heavy-load) lasting approximately 30 minutes, including a 10-minute aerobic-based warm-
up (rowing or cross-trainer) at low-moderate intensity. All sessions were supervised by the author
to ensure consistency of warm-up intensity and order of resistance exercises performed. None of the
participants wore compression sleeves. During the first familiarization session, participants were
30
introduced to four upper extremity exercises consisting of the biceps curl (free weights), followed
by the chest press, latissimus pull down and triceps extension using resistance exercise machines
(Technogym®, Gamettola, Italy). Hereafter, a 1 RM strength test was performed for each exercise.
During the second session, one set of 10-15 repetitions was performed, followed by a new 1 RM
strength test. Subsequent resistance exercise prescription during the experimental sessions was
based on these values. Women then participated in the experimental sessions (performed on the
same day of the week and at the same time of day) and were instructed to maintain normal upper-
body activities and to refrain from extraordinary activities involving the upper extremities.
Resistance exercise load corresponded to 60-65% 1 RM (2 sets of 15-20 repetitions) for the low-
load session and 85-90% 1 RM (3 sets of 5-8 repetitions) for the heavy-load session. Participants
were instructed to work to muscle fatigue (until they were unable to maintain appropriate technique)
within the prescribed range, with rest periods of 60-90 seconds between sets.
Study 3
Following baseline testing, all participants received verbal and written information, highlighting
current evidence-based risk factors for developing BCRL (e.g. lymph node removal, BMI, physical
inactivity). Both groups received health promotion counselling including exploration of barriers
and motivators for adopting regular physical activity as well as clinical advice concerning symptom
management and feedback regarding physiological outcomes (64).
HIGH group
Participants randomized to the HIGH group participated in a twelve-week, group-based exercise
program, supervised by a cancer nurse specialist and a physical therapist. The first six weeks
consisted of Body & Cancer (61, 64) followed by six weeks of an ‘All sport’ exercise program. The
‘All sport’ program focused on moderate to high intensity aerobic activities and the high-intensity
components of the previous six weeks (Table 4) (64). The resistance exercise program in Body &
Cancer was carried out as previously described with resistance exercise loads adjusted every third
week, based on new 1 RM testing to ensure progression. If participants developed signs of BCRL or
experienced exacerbations of an existing BCRL, they were instructed to refrain from resistance
exercise targeting the upper extremities or to decrease loads.
LOW group
The LOW group participated in an individualized, home-based, twelve-week walking program
supported by a pedometer and counselling from a cancer nurse specialist or physical therapist
(Table 4). Participants were issued an Omron Walking Style Pro pedometer 2.0, and were
31
encouraged to progressively increase steps to ultimately achieve 10,000 steps per day. Face-to-face
meetings during weeks 2, 4, 6, 9 and 12 were held to discuss daily walking targets as well as
barriers and motivators for achieving these targets. Participants were also encouraged to exercise
(beyond walking) and to integrate physical activity into activities of daily living.
Measurement methods/outcomes
Study 1
Medical records
Data regarding surgery and treatment as well as BCRL, recurrent cancer and mortality status were
obtained from electronic medical records.
Structured telephone interview
Structured telephone interviews, lasting 15 minutes on average, were conducted within a six week
period by the PhD student. The primary outcome, a clinical diagnosis of BCRL, was recorded if the
participant answered “yes” to having been diagnosed with lymphedema. Subsequently, participants
were asked when and by whom the diagnosis was made, as well as which region was affected
(hand, arm, breast, torso). Demographic, treatment, and physical activity characteristics were also
HIGH intervention
Monday Tuesday Wednesday Thursday Friday
Part I:Body & Cancer 6 weeks, 9 h/week
Aerobic and resistance
exercise (1.5 h)
Relaxation (0.5 h)
Swedish massage (0.5 h)
Body awareness (1.5 h)
Relaxation (0.5 h)
Aerobic and resistance
exercise (2 h)
Relaxation (0.5 h)
Aerobic and resistance
exercise (1.5 h)
Relaxation (0.5 h)
Swedish massage (0.5 h)
Part II: ‘All-sport’ 6 weeks, 6 h/week
Aerobic and resistance
exercise and e.g.
ballgames, dancing (2 h)
Aerobic and resistance
exercise and e.g.
ballgames, dancing (2 h)
Aerobic and resistance
exercise and e.g. ballgames,
dancing (2 h)
LOW intervention
Week 1
Pedometer Week 2
Pedometer Week 4
Pedometer Week 6
Pedometer Week 9
Pedometer Week 12
Pedometer
consultation consultation consultation consultation consultation consultation
Both interventions
Baseline Week 6 Week 12 Week 39
Health promotion counselling Health promotion counselling Health promotion counselling Health promotion counselling
Table 4. Overview of HIGH and LOW interventions
32
obtained as well as any information lacking from the medical records. Specifically, demographic
characteristics included age, current BMI, relationship status, age of children living at home,
education and current occupation. Treatment characteristics included whether surgery had been
performed on the dominant side and whether they had been introduced to breast cancer-specific
post-operative exercises. Behavioral characteristics included whether the participant had performed
post-operative exercises before participating in Body & Cancer, whether they had engaged in
resistance exercise 1-3x/week between surgery and Body & Cancer, and whether they had engaged
in resistance exercise1-3x/week post intervention, and if so for how long, and with what load(s). In
addition, leisure time physical activity was explored using the Salting-Grimby Physical Activity
Level Scale (65).
Arm Circumference measurements
For participants who answered “yes” to having been diagnosed with BCRL, circumference
measurements from the time of lymphedema assessment were obtained from medical records or by
contacting the clinician that had diagnosed BCRL. No standardized protocol for measuring BCRL
was used, with clinicians using measurement protocols ranging from five to seven measuring
points. For this study, a participant was considered to have BCRL if an inter-arm difference of ≥ 2
cm at to two or more measures was reported (66).
Body & Cancer database
Baseline BMI and pre-illness physical activity levels (65) were obtained from the database, as well
as baseline and post-intervention muscular strength (1 RM) of the upper and lower extremities
(chest and leg press, respectively) and adherence to the Body & Cancer program.
Study 2
All outcomes were assessed pre-, immediately post- (within 30 minutes) and 24- and 72-hours post-
resistance exercise sessions.
Extracellular fluid
Bioimpedance spectroscopy (BIS) (SFB7, Impedimed, Brisbane, Australia) was performed
immediately after the DXA scans. This measurement method has a high reliability for detecting
sub-clinical BCRL (67, 68) by directly measuring and comparing the impedance of extracellular
fluid in the upper extremities to electrical currents at a range of frequencies (68). Participants were
positioned in supine with arms and legs slightly abducted with palms facing down. Using the
principle of equipotentials, four single tab electrodes were placed in a tetrapolar arrangement.
Measurement electrodes were placed on the dorsum of the wrist midway between the styloid
33
processes. Current drive electrodes were placed five centimeters distally on the dorsal side over the
third metacarpal of the hand, and approximately midway on the third metatarsal on the dorsum of
the foot (69). The ratio of impedance (at R0) between the at-risk and non-affected arm was
calculated and converted into an L-Dex score taking arm dominance into account (70).
Inter-arm volume % difference
Measurements of arm volume were obtained using Dual energy x-ray absorptiometry (DXA) (Lunar
Prodigy Advanced Scanner, GE Healthcare, Madison, WI). DXA measures tissue composition
using a three-compartment model that is sensitive to changes in upper extremity tissue composition
(71). Using previously derived densities for fat (0.9 g/ml), lean mass (1.1g/ml) and bone mineral
content (1.85 g/ml), DXA measurements were converted into estimated arm volumes. Lying supine
on the scan-table with the arm separated from the trunk, each arm was scanned separately. If
necessary, a Velcro band or the free arm was placed over the breast to ensure space between the
arm and trunk. Small animal software (ENCORE version 14.10) was used to analyze the scans as
described by Gjorup et al., (71). All scans were point typed and analyzed by a clinical expert. Inter-
arm volume % differences (at-risk arm minus unaffected arm/unaffected arm * 100) were then
calculated for each participant.
Subjective assessment of BCRL symptoms
The severity of BCRL symptoms (swelling, heaviness, pain, tightness) was monitored using a
numeric rating scale (NRS). Participants rated their perception of symptoms for each arm on a scale
from 0 (no discomfort) to 10 (very severe discomfort) (72, 73).
Study 3
All outcomes were assessed at baseline, 12 week follow-up (immediately post-intervention) and 39
week follow-up. 1 RM strength and self-reported data were also assessed at these time points as
well as at 6 weeks post-baseline.
Extracellular Fluid
BIS was performed immediately after DXA as described in Study 2, and was consecutively
obtained from participant 71 forward.
Inter-arm volume % difference
Arm volume was obtained using DXA. Lying supine on the scan-table with arms slightly abducted
and hands in a mid-prone position, total body scans were performed fasting, at the same time of day
(mornings) at all assessments. Scans were automatically analyzed using encore version 16, GE
Healthcare Lunar software. From the total body scans, the measured weight of fat, lean mass and
34
bone mineral content of both arms were identified and converted into estimated arm volumes as in
Study 2 with the region of interest extending from the gleno-humeral joint to the finger tips (74,
75). Inter-arm volume % differences (at-risk arm minus unaffected arm/unaffected arm * 100) were
then calculated for each participant.
Self-reported BCRL symptoms
The severity of BCRL symptoms (heaviness, tightness, pain, swelling) on the surgical side was
monitored using a NRS. Participants rated their perception of symptoms on the surgical side as
compared to the non-surgical side on a scale from 0 (no discomfort) to 10 (very severe
discomfort)(72).
Self-reported swelling
Participants reported if they had observed a difference in size between their surgical-and non-
surgical side within the last week. If they answered “yes”, they were then asked to report where:
fingers, hand, forearm, upper arm (extremity) and breast, torso (body).
Upper extremity muscular strength
To assess maximal strength of the upper extremities, the 1 RM strength test (51) was performed
using the chest press (Technogym®, Gamettola, Italy). Prior to the 1 RM attempt, a warm-up was
performed consisting of 8-10 repetitions using a low weight ensuring no muscle fatigue. Hereafter,
load was increased based on ease of performance, with one repetition lifted of each load, until the
participant was unable to lift a respective load.
Breast cancer-specific functional and symptom domains
To assess breast cancer-specific quality of life domains (functional and symptom), the 23 item
European Organization for Research and Treatment of Cancer (EORTC) breast cancer module
(BR23) (76), version 3.0, was used. This validated breast cancer-specific module includes four
functional scales as well as four symptom specific subscales. Each item is scored on a four point
Likert scale from “not at all” to “very much”, with raw scores summed and converted to a score out
of 100. Higher levels of functioning are represented by higher functional scores and worse
symptoms are represented by higher symptom scores (76, 77).
Data analysis
Statistical assistance was provided by associate professor, senior statistician Karl B. Christensen
(Department of Biostatistics, University of Copenhagen) for all three studies, with additional
assistance from PhD Megan L. Steele (Institute of Health and Biomedical Innovation, Queensland
35
University of Technology) in study 2. A two-tailed P < .05 was taken as evidence of statistical
significance.
Study 1
Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) software
(version 19) for Windows. Descriptive statistics are presented as counts (percentages) for
categorical variables and as means and standard error (SE) for continuous variables unless
otherwise noted. Mean changes in 1 RM muscular strength post Body & Cancer were assessed
using a paired t-test, and were analyzed on a per-protocol basis, (only participants with data at
baseline and 6 weeks) as well as on an intention to treat (ITT) basis using baseline observation
carried forward. Point prevalence of BCRL was calculated on average 14 months post intervention
(range 4 to 26 months)), and estimated retrospectively at the commencement of Body & Cancer as
well as 1, 2, 3, and 4 months post Body & Cancer.
To compare differences between participants diagnosed with BCRL and those
without, Chi-squared and Fisher’s exact test were used for categorical variables and two-sample t-
tests for continuous variables. Levene’s test for equality of variances was performed and results
presented use pooled variances unless otherwise noted.
Study 2
Sample size calculation was based on changes in L-Dex scores between baseline and 72-hours post-
resistance exercise sessions. On the basis of clinical experience with patients with BCRL a change
score of 2.0 L-Dex units was considered clinically relevant, and SD of the distribution of L-Dex
units was estimated at 1.9 units based on results of Cormie et al.(12). However, upon study
initiation no normative data existed in the at-risk population nor did a threshold for a clinically
significant acute change. As such, a change in 2.0 L-Dex units was deemed too small in the at-risk
population, based on the assumption that larger fluctuations would be seen within the normal range.
Therefore, a priori, the clinically relevant threshold was set at 3.0 L-Dex units. Eighteen
participants were needed to be 90% sure that the limits of a two one-sided 95% confidence interval
(CI) would exclude a difference in means of more than 3.0 L-Dex units. To allow for drop-outs, 21
women were recruited.
Descriptive statistics included counts (and percentages) for categorical values and
mean ± standard deviation (SD) for normally distributed continuous variables, unless otherwise
noted. Individual responses to resistance exercise loads were first assessed descriptively, including
determination of the proportion that exceeded the predetermined clinically relevant threshold. Next,
36
generalized estimating equations (GEE) (78) were used to evaluate the effects of time (pre-, post-,
24- and 72-hours post) and load (low-/heavy-load), and a time x load interaction. An exchangeable
correlation structure was used to model the within-subject correlation of repeated measurements
over time and across intensities.
To assess equivalence, a priori, equivalence margins were determined for all
outcomes. For extracellular fluid, the margin of equivalence was set at ± 3.0 L-Dex units (primary
outcome). An equivalence margin of ±3.0% was used for inter-arm volume % differences based on
findings from Stout et al., (79) showing that volume increases of >3% from pre-operative measures
were indicative of subclinical BCRL. For all BCRL symptoms, inter-arm differences were
calculated and an equivalence margin was set at ±1.0 points based on previous findings that suggest
a 2 point or 30% change to be clinically meaningful for pain (72). The principle of confidence
interval inclusion was used to calculate two one-sided upper and lower 95% confidence limits for
all outcomes (80) (reported as two-sided 90% confidence limits). If the interval between the upper
and lower confidence limits was within the predetermined equivalence margin, equivalence
between resistance exercise intensities was declared. Per-protocol principles were applied as this is
considered the most conservative approach for determining equivalence (81). Analyses were
conducted in R version 3.3.1 (82) using geepack 1.2.0.1 for GEE modelling (83).
Study 3
Analyses were conducted using Statistical Analysis Software (SAS) version 9.4.
Descriptive statistics included counts (and percentages) for categorical variables and point
prevalence of BCRL defined as L-Dex > 10, inter-arm volume difference > 5% or self-reported
observation of swelling. For continuous variables means ± SD (normally distributed), or median
with interquartile range (IQR) (not normally distributed) are presented.
Linear mixed models with a heterogeneous autoregressive (1) covariance structure
were used to estimate changes over time in each group with an intention-to-treat (ITT) approach.
An exchangeable correlation structure modelled the within-subject correlation of repeated
measurements over time and across interventions, incorporating all available data including
participants with incomplete data. Effect sizes were calculated for muscular strength (84). A two-
sided significance level was set at 0.05 for outcomes where superiority was hypothesized (muscular
strength and cancer-specific functional and symptom domains).
As with Study 2, a priori, clinically relevant equivalence margins were chosen for BCRL outcomes.
For L-Dex, the margin of equivalence was set at ±5.0 units based on new normative data indicating
37
that L-Dex scores fluctuate between 9-11 units (70). An equivalence margin of ±3.0% was used for
inter-arm volume % differences and at ±1.0 points for BCRL symptoms, and the principle of
confidence interval inclusion (80) was used to calculate two one-sided upper and lower 95%
confidence limits, (reported as 90% confidence limits) as in study 2. Further, a per-protocol analysis
of participants with an adherence rate >65% to the HIGH intervention was performed to evaluate
equivalence of BCRL outcomes to the predetermined equivalence margins.
Ethical approval
Study 1
Study 1 was performed in accordance with the Helsinki Declaration, and approved by the Danish
Data Protection Agency.
Study 2
Study 2 was registered at Current Controlled Trials (ISRCTN97332727), approved by the Danish
Data Protection Agency (30-1430) and the Danish Capital Regional Ethics Committee (H-3-2014-
147).
Study 3
Study 3 was registered at Current Controlled Trials (ISRCTN24901641), approved by the Danish
Data Protection Agency (2011-41-6349) and the Danish Capital Regional Ethics Committee (H-1-
2011-131).
Results
The following section presents the main findings of the three studies.
Study 1
Participants
The mean age of participants was 47.7 years and mean self-reported BMI was 24.1, with 54 (36%)
classified as overweight (BMI > 25). The majority reported being physically active before diagnosis
108 (72%). All had undergone chemotherapy, with 141 (95%) having received adjuvant taxane-
based chemotherapy, 62 (42%) had received a mastectomy and 90 (60%) had ALND while 120
(81%) had received radiotherapy.
38
Body & Cancer participation
Over half of the participants (60%) had an adherence rate of at least 70% (17 of 24 training days).
Significant increases in lower and upper extremity muscular strength were observed after six weeks
of training (Table 5).
Total Population Total Population ALND Population
Baseline 6 weeks Change No BCRL BCRL No BCRL BCRL
1 RM (kg) n Mean (SE) Mean (SE) Mean (SE) n ∆ Mean (SE) n ∆ Mean (SE) n ∆ Mean (SE) n ∆ Mean (SE)
Chest Press 125 27.2 (.66) 31.9 (.70) 4.7 (.43) 93 4.6 (.47) 32 5.0 (.98) 41 4.3 (.69) 31 4.5 (.88)
Leg Press 132 76.0 (2.00) 94.8 (2.45) 18.8 (1.75) 96 16.5 (1.82) 36 24.7 (4.07) 45 14.9 (2.48) 35 23.7 (4.06)
BCRL point prevalence
At an average follow-up of 14 months (range 4-26) post Body & Cancer, point prevalence of BCRL
was 27.5% for the total sample (n=149). When analysis was restricted to include only women who
underwent ALND, point prevalence was 44.4% (Table 6). Six percent of the total sample and 10%
of those who underwent ALND reported that they had been diagnosed with BCRL during the
intervention, with an additional 11.4% and 17.8% diagnosed within the first four months post Body
& Cancer, respectively. All BCRL cases had ALND, with the exception of one participant (n = 89,
98.8%). Of the participants with a diagnosis of BCRL, one reported swelling in the hand only, three
in the breast only, and one in the torso only. The remainder (n = 144) reported swelling in the arm
only or in combination with the hand, breast and torso.
Arm circumference measurements were obtained for 38 of the 41 (93%) participants
diagnosed with BCRL, from two hospitals and six private practice lymphedema therapists. Of these,
47.4% had an inter-arm difference ≥ 2 cm at two or more measures. Therefore, when applying this
measurement method and cut-off, prevalence rates were lower than for those diagnosed with BCRL
(Table 6).
Table 5. Muscular strength post Body & Cancer
∆ Change between baseline and post Body & Cancer, Bold (p-value <0.05), No BCRL as reference
39
BCRL vs. No BCRL
When comparing characteristics of participants with and without diagnosed BCRL, significantly
more (p < 0.05) participants with BCRL currently had a BMI > 25 (BCRL 21 (51%) vs. No BCRL
33 (31%), had undergone ALND (BCRL 40 (98%) vs. No BCRL 50 (46%)) and had received
radiotherapy (BCRL 39 (95%) vs. No BCRL 81 (75%)). No between group differences were
observed in regard to resistance exercise participation before or after Body & Cancer, nor to
adherence to Body & Cancer, or to changes in muscular strength (Table 5).
A sub-analysis of participants with ALND showed that significantly more (p < 0.05)
participants with BCRL were currently overweight or had been overweight upon commencing Body
& Cancer (Table 7). No between group differences were found in regard to radiotherapy, however
93.3% of the participants with ALND had received radiotherapy. No between group differences
were seen in regard to RE participation before or after Body & Cancer (Table 7), nor to changes in
muscular strength (Table 5).
Time in relation to participation in
Body & Cancer Diagnosed BCRL
Total population
(n = 149)
Circumference ≥ 2
Total population
(n = 146)†
Diagnosed BCRL
ALND population
(n = 90)
Circumference ≥ 2
ALND population
(n = 87)†
During intervention 9 (6.0) 5 (3.4) 9 (10.0) 5 (5.8)
Within 1month post intervention 16 (10.7) 10 (6.8) 16 (17.8) 10 (11.5)
1-2 months post intervention 21 (14.1) 11 (7.5) 21 (23.3) 10 (11.5)
2-3 months post intervention 23 (15.4) 13 (8.9) 23 (25.6) 12 (13.7)
3-4 months post intervention 26 (17.4) 15 (10.3) 25 (27.8) 14 (16.1)
Total at study* 41 (27.5) 18 (12.3) 40 (44.4) 17 (19.5)
Table 6. Point prevalence of lymphedema in relation to participation in Body & Cancer. Values are
numbers of participants (%).
*On average 14 months (4-26) post Body & Cancer. † Circumference measurements not available for 3 participants
40
No BCRL
(n = 50)
BCRL
(n = 40)
Demographic characteristics p
Age (years) mean (SD) 49.2 (9.0) 47.8 (8.0) .436
Children in care < 7 years 9 (18.0) 4 (10.0) .371
Married, cohabitating or in a relationship 37 (74.0) 28 (70.0) .813
Education > secondary school 44 (88.0) 37 (92.5) .726
Employed (full/part time) 40 (80.0) 29 (72.5) .458
Not physically demanding work 27 (54.0) 19 (47.5) .832
Moderately physically demanding work 11 (22.0) 9 (22.5)
Very physically demanding work 2 (4.0) 1 (2.5)
Health and medical characteristics
Baseline BMI (kg/m2) > 25* 13 (26.0) 20 (51.3) .017
Study BMI (kg/m2) > 25 9 (18.0) 21 (52.5) .001
Mastectomy 25 (50.0) 18 (45.0) .676
Non-dominant arm 32 (64.0) 23 (57.5) .664
Chemotherapy
3-wkly CE x 3 -> 3 wkly docetaxel x 3 33 (66.0) 29 (72.5) .508
3-weekly CT x 6 13 (26.0) 10 (25.0)
Other 4 (8.0) 1 (2.5)
Received radiotherapy 46 (92.0) 38 (95.0) .689
Received endocrine treatment 45 (90.0) 33 (82.5) .358
Received trastuzumubab 8 (16.0) 2 (5.0) .175
Physical activity level (self-reported)
Pre-illness†
Sedentary 1 (2.1) 1 (2.8) .717
Walking or cycling for pleasure 11 (22.9) 9 (25.0)
Regular physical exercise, at least 3 h/week 34 (70.8) 23 (63.9)
Intense physical activity > 4 h/week 2 (4.2) 3 (8.3)
Present
Sedentary 0 (0.0) 1 (2.5) .326
Walking or cycling for pleasure 7 (14.0) 10 (25.0)
Regular physical exercise at least 3 h/week 25 (50.0) 15 (37.5)
Intense physical activity > 4 h/week 18 (36.0) 14 (35.0)
Training
Performed exercises prescribed post-surgery‡
No 10 (21.7) 3 (7.7) .192
3 x weekly 8 (17.4) 7 (17.9)
Daily 28 (60.9) 29 (74.4)
RE 1-3x/wk between surgery and Body & Cancer ‡ 13 (28.3) 10 (25.6) 1.000
RE 1-3x/wk 3 months after Body & Cancer 24 (48.0) 22 (55.0) .532
Utilized 2-3 sets of 5-8 RM 14 (28.0) 14 (35.0) .769
Adherence ≥70% while in Body & Cancer 35 (70.0) 19 (47.5) .051
Table 7. BCRL vs. no BCRL in participants with ALND (n = 90). Values are numbers (%)
unless stated otherwise.
Abbreviations: CE, cyclophosphamide & epirubicin; CT, cyclophosphamide & docetaxel; RE, resistance
exercise *(n = 84, (n = 39 BCRL; n = 50 no BCRL) due to missing data. †(n = 84) due to missing data.‡ (n =
85,(n = 39 BCRL; n = 46 no BCRL) participants receiving neo-adjuvant (n = 4) or chemotherapy for advanced
disease (n = 1) not included.
41
Study 2
Participants
Twenty one eligible participants were included in the study with seventeen (81%) completing all
data collections. For details of participant flow see Figure 4. Characteristics of the study population
are presented in Table 8. As per eligibility criteria, all participants received adjuvant taxane-based
chemotherapy during the experimental sessions. However, as standard chemotherapy changed
midway through the study period, the first ten participants received docetaxel, while the last 11
received paclitaxel.
Variables Mean ± SD / Median (range)
Age (years) 45.3 ± 9.2 / 46 (23-60)
BMI (kg/m2) 25.3 ± 4.7
Cancer stage n (%)
ll 15 (71)
lll 6 (29)
Tumor size (mm) 21.5 ± 12.9 / 18 (7-62)
Breast surgery n (%)
Lumpectomy 8 (38)
Mastectomy 13 (62)
Surgery on dominant side n (%) 11 (52)
Axillary lymph nodes removed 21.7 ± 7.8
Metastatic lymph nodesa 5.7 ± 7 / 2 (1-25)
Seroma drainage n (%) 5.5 ± 3.4
Chemotherapy n (%)
3-wkly CE x 3 -> 3 wkly docetaxel x 3 10 (48)
3-wkly CE x 3 -> 1 wkly paclitaxel x 9 11 (52)
Axillary webbing at screening n (%) 8 (38)
L-Dex at screening -0.08 ± 2.23
Table 8. Characteristics of participants (n = 21)
Abbreviations: CE, cyclophosphamide & epirubicin a) micro- and macrometastases
42
Individual responses to resistance exercise
Individual responses to resistance exercise sessions varied with no apparent group trend observed
for L-Dex and inter-arm volume % differences (Figure 5A, 5B). For BCRL symptoms, most
participants were asymptomatic pre-exercise and remained asymptomatic throughout the
subsequent data collections irrespective of loads lifted (Figure 5C-F).
Subplot A Heavy-load L-Dex pre-, post-, 24-hours (n = 18); Sub-plots C-F Heavy-load breast cancer-related
lymphedema symptoms pre- and post- exercise (n = 18), Sub-plots C-F (n=) refers to the number of participants
with a symptom score of 0 at all time points.
Figure 5. Individual responses related to low- and heavy-load resistance exercise (n = 17)
43
L-Dex
The estimated mean difference between resistance exercise loads and associated two-sided 90% CIs
were within the predetermined equivalence margin of ±3.0 L-Dex units immediately-, and 24-hours
after resistance exercise indicating equivalence between intensities (Table 9). However, at 72-hours
post-exercise, the lower CI exceeded -3.0 and equivalence between low- and heavy-load intensities
could not be declared, indicating a reduction of extracellular fluid post heavy-load resistance
exercise.
Inter-arm volume % difference
Equivalence between resistance exercise loads was observed at all time points for inter-arm volume
% differences, as estimated mean differences and 90% CI were within the ±3.0 margin of
equivalence (Table 9).
BCRL symptoms
Equivalence between resistance exercise loads was found for all BCRL symptoms at all time points,
as estimated mean differences and associated 90% CIs were within the equivalence margin of ±1.0
(Table 9).
Adverse events
No adverse events related to exercise (i.e. sprains or strains) were reported. Two (11%) participants
were advised to seek evaluation by a lymphedema therapist at the end of the study period as L-Dex
scores had exceeded ten (Figure 5A). One participant had a pre-exercise L-Dex score of 7.9 in
week one which remained elevated at week two, with a pre-exercise L-Dex score of 11.7 that
decreased over the subsequent data collections. The other participant initiated the heavy-load
session at week one with a pre-exercise L-Dex score of 3.8, and subsequent measures fluctuating
below 5.0 units. At week two, the pre-exercise L-Dex score had increased to 9.5 that further
increased to 12.7 post-exercise, followed by decreasing subsequent measures. Notably, this
participant suffered from rapid weight gain due to generalized edema between weeks one and two
that was effectively treated with diuretics. All other outcomes were within the predetermined
clinical thresholds at all time points for both of these participants.
44
Estimated mean differenceb
Equivalence 90% CI
L-Dex (±3.0)a
Post- exercise -0.97 -2.09 to 0.16
24-hrs Post-exercise -0,14 -1.63 to 1.35
72-hrs Post-exercise -1.00 -3.17 to 1.17c
Inter-arm volume % difference (±3.0)a
Post- exercise 0,21 -0.89 to 1.31
24-hrs Post-exercise 1,09 0.41 to 1.78
72-hrs Post-exercise 0,96 -0.09 to 2.02
Inter-arm difference Pain (±1.0)a
Post- exercise 0 -0.43 to 0.43
24-hrs Post-exercise -0.06 -0.58 to 0.46
72-hrs Post-exercise -0,06 -0.61 to 0.49
Inter-arm difference Heaviness (±1.0)a
Post- exercise 0,24 -0.23 to 0.70
24-hrs Post-exercise 0,18 -0.32 to 0.67
72-hrs Post-exercise 0,24 -0.38 to 0.85
Inter-arm difference Tightness (±1.0)a
Post- exercise -0,06 -0.45 to 0.34
24-hrs Post-exercise -0.11 -0.50 to 0.27
72-hrs Post-exercise 0.20 -0.37 to 0.77
Inter-arm difference Swelling (±1.0)a
Post- exercise 0 -0.33 to 0.33
24-hrs Post-exercise 0 -0.33 to 0.33
72-hrs Post-exercise 0.06 -0.42 to 0.54
Table 9. Equivalence between resistance exercise intensities (n = 17)
aEquivalence margin. b Estimated mean difference calculated using a generalized estimating equations model with heavy-
load as comparator (heavy minus low). c equivalence not demonstrated
45
Study 3
Participants
391 women receiving adjuvant chemotherapy for breast cancer were screened for eligibility with
153 (39%) included in the study between January 2014 and July 2016 (Figure 4). Baseline
characteristics were balanced between the two intervention groups (Table 10). However, more
participants with L-Dex data had received paclitaxel based chemotherapy (13 (20.3%) vs. 6 (6.7%).
Further, the mean BMI of participants without inter-arm volume data was higher than participants
with, as body dimensions exceeded the DXA scan area (31.3 ± 5.3 vs. 24.3 ± 3.6, respectively).
Characteristics Total (n = 153) HIGH (n = 75) LOW (n = 78)
Age (years), mean ± SD 51.7 ± 9.4 51.5 ± 9.6 52.0 ± 9.3
BMI (kg/m2), mean ± SD 26.1 ± 5.1 26.2 ± 5.3 26.0 ± 4.9
Cancer stage, n (%)
Stage 1
Stage 2
Stage 3
56 (36.6%)
81 (52.9%)
16 (10.5%)
31 (41.3%)
36 (48.0%)
8 (10.7%)
25 (31.1%)
45 (57.7%)
8 (10.3%)
Breast surgery, n (%)
Lumpectomy
Mastectomy
Mastectomy plus expander
90 (58.8%)
56 (36.6%)
7 (4.6%)
47 (62.7%)
26 (34.7%)
2 (2.7%)
43 (55.1%)
30 (38.5%)
5 (6.4%)
Axillary surgery, n (%)
Axillary lymph node dissection
Sentinel node biopsy
61 (39.9%)
92 (60.1%)
26 (34.7%)
49 (65.3%)
35 (44.9%)
43 (55.1%)
Nodes removed, median (IQR) 3 (2-17) 3 (1-15) 5 (2-19)
Surgery on dominant side,* n (%) 76 (49.7%) 39 (52.0%) 37 (47.4%)
No. of seroma drainages, median (IQR) 1 (0-5) 1 (0-5) 1 (0-5)
Chemotherapy, n (%)
3-wkly CE x 3 -> 3 wkly docetaxel x 3
3-wkly CE x 3 -> 1 wkly paclitaxel x 9
Other
130 (85.0%)
19 (12.4%)
4 (2.6%)
66 (86.7%)
8 (10.7%)
1 (1.3%)
64 (82.1%)
11 (14.1%)
3 (3.9%)
Observations of swelling,** n (%)
Extremity (hand, underarm, overarm)
Body (breast, torso)
Both (body & extremity)
5 (3.3%)
31 (20.5%)
11 (7.3%)
2 (2.7%)
14 (18.9%)
3 (4.1%)
3 (3.9%)
17 (22.1%)
8 (10.4%)
Treatment related to lymphedema,** n (%)
Preventatively
Existing lymphedema
4 (2.6%)
5 (3.3%)
1 (1.4%)
1 (1.4%)
3 (3.9%)
4 (5.2%)
Symptom subscales EORTC-BR23
Arm symptoms, n, mean ± SD
Breast symptoms, n, mean ± SD
152, 16.2±19.0
151, 18.9±16.1
74, 15.6±20.1
74, 18.6±16.4
78, 16.8±18.0
77, 19.2±16.0
L-Dexa, n, Mean ± SD 80, -0.3±5.1 39, -0.6±3.6 41, 0.1±6.2
Volume % differenceb, n, mean ± SD 118, 1.3±19.8 55, 0.6 ±19.7 63, 1.9±20.0
Upper extremity strengthc, n, mean ± SD 138, 29.4±8.3 71, 29.0±8.1 67, 29.8±8.
Table 10. Baseline charactereristics (n = 153)
Not included: *n = 4 missing, **n = 2 missing, a n=3 (n = 1 missing, n = 2 bilateral axillary surgery), b n =35 (n = 5 bilateral
axillary surgery, n = 30 left side estimated), c n = 15 (n = 14 post-surgery restrictions, n =1 precautionary due to arm swelling)
Abbreviations: BMI, body mass index; SD, standard deviation; CE, cyclophosphamide & epirubicin; pctl, percentile/IQR,
interquartile range
46
Retention, adherence and adverse events
Outcome data were available for 130 participants (85%) at 12-weeks post-intervention, and for 121
(79%) at the 39 week follow-up (Figure 1). %). Four women never partook in the intervention and
an additional six withdrew shortly after initiation of the program. A detailed description of reasons
for non-attendance can be found elsewhere (article in submission, Møller et al.).
On average, participants in the HIGH group attended 66% (±18) of the planned
exercise sessions. Adherence to resistance exercise prescription of the upper extremity
corresponded to a median load of 10 RM during the first two weeks. From week three forward
(heavy-load period), loads corresponded to 7 RM. Comparatively, loads lifted for the leg press were
14 RM and 8 RM, respectively. No exercise-related injuries were reported. Six participants in the
HIGH and five participants in the LOW group experienced swelling during the 12-week
intervention and received treatment delivered by a lymphedema therapist. Just one of the women in
the HIGH group reduced loads (10-15 RM), whereas the other five continued lifting loads
corresponding to 5-8 RM. Seven of these participants had received treatment for BCRL between
the 12 and 39 week follow up, while three had not, and one was lost-to follow-up at 39 weeks.
Lymphedema
Point prevalence: Irrespective of assessment method, point prevalence of BCRL was similar
between the HIGH and LOW group at all time points (Table 11). Point prevalence of BCRL varied
depending on the method of assessment. For participants reporting an observation of swelling on
the surgical side compared to the non-surgical side, it is worth noting that body only (breast and
torso) accounted for 31 (66%), 8 (25.8%) and 17 (39.5%) of these cases at baseline, 12 and 39
weeks respectively. As BIS and DXA detect arm and hand swelling only, these methods of
lymphedema were unable to detect these cases (Table 11).
47
Self-reported diagnosis of BCRL at baseline: Five participants (3.3%) reported a diagnosis
of BCRL which they were receiving or had received lymphedema treatment for; one of whom
participated in the HIGH group and carried out the resistance exercise protocol without need for
modification (e.g. less load). All five of these participants also reported observed swelling at
baseline, two of whom reported localization to the torso only, which therefore could not be detected
by BIS or DXA. Further, no DXA measurements were available for two participants as body
dimensions exceeded the scan areas. Comparatively, one of these participants had an L-Dex >10,
while no L-Dex was available for the other participant. Finally, one of the participants reported
observed swelling of the overarm, breast and torso which BIS and DXA did not detect.
L-Dex: The mean difference in L-Dex scores between the HIGH and LOW group and associated
two-sided 90% CIs were contained within the predetermined equivalence margin of ±5.0 units at
both 12 and 39 weeks indicating equivalence between groups (Table 12). Equivalence to the
predetermined equivalence margin in the per-protocol analysis at 12 weeks was also observed
(Table 13). However, at the 39 week follow-up, the upper CI exceeded the predetermined margin.
n Baseline n 12 weeks n 39 weeks
L-Dex >10a
HIGH
LOW
39
41
0 (0.0%)
2 (4.9%)
33
31
3 (9.1%)
2 (6.5%)
41
34
4 (9.8%)
3 (8.8%)
Inter-arm volume % difference > 5%b
HIGH
LOW
55
63
15 (27.3%)
15 (23.8%)
45
51
14 (31.1%)
13 (25.5%)
50
49
12 (24.0%)
13 (26.5%)
Observed difference in size between sides within the last weekc
HIGH
LOW
74
77
19 (25.7%)
28 (36.4%)
62
63
18 (29.0%)
13 (20.6%)
62
59
21 (33.9%)
22 (37.3%)
Based on all available data for each outcome.a Maximum n = 81 due to bilateral axillary surgery (n =2) and
BIS not available (n = 70). At 39 weeks BIS was available for twelve of these particicpants and included in
the analysis ; b Maximum n = 148 due to bilateral axillary surgery (n = 5), n = 30, 28, 14 exceeded DXA
scan area, respectively at baseline, 12 and 39 weeks and were therefore not included in the analysis); c Of
the participants that observed swelling at: baseline n = 31 (66%), 12 weeks n = 8 (25.8%), 39 weeks n = 17
(39.5%) reported swelling located to the body (breast , torso) only
Table 11. Lymphedema point prevalence. Number of participants (%)
48
Inter-arm volume % difference: Non-equivalence between groups was observed at all time
points for inter-arm volume % differences with deviations inconclusive or indicating reductions in
arm volume, favoring the HIGH group (Table 12). These observations were consistent with findings
from the per-protocol analysis (Table 13).
BCRL symptoms: Equivalence between groups was found for all symptoms except for pain at 12
weeks and tightness and pain at 39 weeks favoring reductions for those in the HIGH group (Table
12). Consistent with the between group analysis, the per-protocol findings indicated equivalence to
the predetermined margin or deviations indicating reductions in symptoms except for pain at 39
weeks as upper CI’s exceeded the equivalence margin (Table 13).
Mean difference*
Equivalence 90% CI
L-Dex (±5.0)a (n =81)** n
12 weeks 64 0.4 -2.5 to 3.2
39 weeks 63 0.7 -2.2 to 3.6
Inter-arm volume % difference (±3.0)a (n =148)**
12 weeksǂ 86 -3.5 -17.3 to 10.3b
39 weeksǂ 83 -1.7 -7.7 to 4.3c
Pain (±1.0)a
(n =153)**
12 weeks 124 -0.7 -1.3 to 0b
39 weeks 121 -0.8 -1.5 to -0.1b
Heaviness (±1.0)a
(n =153)**
12 weeks 124 -0.2 -0.6 to 0.2
39 weeks 121 0.0 -0.7 to 0.6
Tightness (±1.0)a
(n =153)**
12 weeks 124 -0.1 -0.8 to 0.6
39 weeks 121 -1.0 -1.8 to 0.2b
Swelling (±1.0)a
(n =153)**
12 weeks 124 0.2 -0.4 to 0.8
39 weeks 120 0.0 -0.8 to 0.7
Table 12. Equivalence between groups for BCRL outcomes
*Mean difference between groups with HIGH as comparator (HIGH minus LOW); **Maximum n; ǂn = 38 and 30 not included at 12 and 39 weeks respectively, due to body dimension exceeding the
DXA scan area; aPre-determined equivalence margin; Bold = equivalence not demonstrated; bnegative deviation reflecting reductions beyond the equivalence margin favoring the HIGH group cinconclusive as mean is within predetermined equivalence margin, but CI’s exceed at both sides
49
Variable Baseline 12 weeks 39 weeks 12 weeks - baseline 39 weeks-baseline
Mean (SD) Mean (SD) Mean (SD) n Δ (90 % CI) n Δ (90 % CI)
L-Dex (±5.0)a
-0.8 (3.3) 0.9 (6.6) 1.5 (5.3) 21* 1.7 (-0.8 to 4.2) 21* 3.2 (0.9 to 5.5)c
Inter-arm volume %
difference (±3.0)a
5.3 (23.0) 4.3 (27.2) 0.6 (7.4) 21** -3.1 (-19.5 to 13.4)b 26** -5.0 (-12.8 to 2.9)b
Pain (±1.0)a
1.0 (1.7) 0.6 (1.2) 1.4 (2.5) 32 -0.4 (-0.9 to 0.1) 33 0.4 (-0.4 to 1.2)c
Heaviness (±1.0)a
0.5 (1.3) 0.3 (1.1) 0.9 (1.7) 32 -0.2 (-0.4 to 0.1) 33 0.4 (0.0 to 0.8)
Tightness (±1.0)a
1.6 (2.4) 0.8 (1.9) 0.4 (0.8) 32 -0.9 (-1.5 to -0.2)b 33 -1.2 (-2.0 to -0.5)b
Swelling (±1.0)a
1.1 (2.0) 1.0 (1.8) 1.0 (1.8) 32 -0.1 (-0.7 to 0.6) 33 -0.1 (-0.6 to 0.5)
Upper extremity muscular strength
A significant (p < 0.05) increase in maximal upper extremity strength was observed in the HIGH
group at all follow-up assessments which were significantly greater compared to those in the LOW
group at 6 and 12 week follow-up (Table 14). Strength increases corresponded to an effect size of
0.55 (95% CI 0.40 – 0.75), 0.55 (0.35 – 0.70) and 0.35 (0.15 – 0.55) at 6, 12 and 39 weeks,
respectively.
Breast cancer-specific functional and symptom domains
No between group differences were observed for any subscale score of the EORTC QLQ-BR23.
However, both groups reported declines in breast symptoms at 6 and 12 weeks. Similarly, declines
in arm symptoms were seen for both groups at 6 weeks, but only in the HIGH group at 12 week
follow-up (Table 14 and Supplemental table).
Table 13. Per-protocol equivalence of BCRL outcomes in participants with >65% adherence to HIGH
a Pre-determined equivalence margin; *maximum n = 21; Bold = equivalence not demonstrated;**maximum n = 32; b negative
deviation reflecting reductions beyond the equivalence margin; c positive deviation reflecting increases beyond the equivalence
50
Δ 6 weeks-baseline Δ 12 weeks-baseline Δ 39 weeks-baseline
Variable n
Mean Δ
(95% CI)
Group difference
(95% CI) n
Mean Δ
(95% CI)
Group difference
(95% CI) n
Mean Δ
(95% CI)
Group difference
(95% CI) Muscular strength 1 RM (kg)*
Chest press
HIGH LOW
58 51
5 (3 to 6)
1 (-1 to 2)
4 (2 to 6)
56 55
4 (3 to 6)
1 (0 to 3)
3 (1 to 5)
50 44
3 (1 to 5)
1 (-1 to 3)
2 (0 to 5)
EORTC QLQ-BR23 scores**
Body Image HIGH
LOW
62
61
2 (-3 to 7)
-1 (-6 to 3)
4 (-3 to 10)
60
62
-3 (-9 to 2)
-6 (-11 to -1)
2 (-5 to 10)
61
56
7 (2 to 11)a
6 (1 to 11)a
1 (-6 to 8)
Systemic therapy ǂ HIGH
LOW
63
62
5 (1 to 10)a
4 (-1 to 9)
1 (-6 to 8)
61
65
7 (2 to 12)a
9 (4 to 14)a
-2 (-9 to 6)
61
57
-19 (-23 to -15)b
-20 (-24 to -16)c
1 (-5 to 7)
Breast symptoms HIGH
LOW
62
62
-6 (-9 to -2)a
-7 (10 to -3)a
1 (-4 to 6)
60
64
-11 (-15 to -7)b
-9 (-12 to -5)a
-2 (-8 to 3)
59
55
-4 (-9 to 1)
1 (-4 to 6)
-4 (-12 to
3)
Arm symptoms HIGH
LOW
62
62
-4 (-8 to 0)a
-5 (-10 to -1)a
1 (-5 to 7)
60
65
-6 (-10 to -1)a
-4 (-8 to 1)
-2 (-8 to 4)
59
56
-1 (-6 to 4)
3 (-2 to 9)
-4 (-12 to
3)
Discussion This thesis examined for the first time whether participation in heavy-load resistance exercise
exacerbates development of lymphedema in breast cancer survivors at risk for lymphedema. This
section provides a discussion of the main findings of the three studies/ four articles considered in
the context of relevant literature. Further, methodological considerations including issues of internal
and external validity will be addressed.
Lymphedema
Findings of Study 1 indicated no association between participation in a multimodal exercise
intervention including heavy-load resistance exercise during taxane-based chemotherapy and BCRL
development. While no conclusions regarding the safety of heavy-load resistance and BCRL could
Table 14. Changes in upper extremity strength and breast cancer-specific functional and symptom domains
Abbreviations: CI, confidence interval; Bold = statistical difference (p <0.05); *No upper extremity strength
measures on one participant (LOW) at baseline due to visible and untreated swelling. No upper extremity strength
assessment at subsequent data collections as the participant was receiving treatment for lymphedema. Three
participants (2 HIGH, 1 LOW) were not assessed for upper extremity strength at 6, 12 and 39 weeks, as a
precautionary measure due to swelling or because participants refused. An additional participant (HIGH) received
treatment for lymphedema at 12 and 39 weeks and was therefore not tested; **Higher functional scores (body
image) indicate higher levels of functioning, lower symptom scores (systemic therapy, arm and breast symptoms)
indicate a reduction in symptoms; ǂ Perceived treatment burden; a, b, c Subjective significance of changes from
baseline in terms of a “small”, b “moderate”, c “large” (Osoba, 1998)
51
be drawn from the conclusions of Study 1, it provided a platform for Studies 2 and 3 to
prospectively evaluate the lymphatic response to heavy-load resistance exercise both acutely after a
single bout of resistance exercise, and after repeated exposure over twelve weeks. In accordance
with the hypothesis, Study 2 found that acute changes in extracellular fluid, arm volume and
symptoms associated with BCRL were similar irrespective of whether low- or heavy-load upper
extremity resistance exercise was performed at all time points with the exception of extracellular
fluid at 72-hours post-exercise, with lower CI’s indicating reductions in swelling after heavy loads.
Further, though individual fluctuations beyond the predetermined thresholds were observed for
BCRL symptoms, the majority of deviations (82%) indicated reductions in severity after resistance
exercise with both intensities. Consistent with the results of Study 2, similar L-Dex scores and self-
reported perceptions of heaviness, swelling and tightness post-intervention were found between the
HIGH and LOW group in Study 3. Additionally, though equivalence was not demonstrated in inter-
arm volume % differences or pain, negative deviations indicated reductions of these outcomes,
favoring the HIGH group. Accordingly, per-protocol analysis of HIGH participants with >65%
adherence also supported equivalence to- or reductions beyond the predetermined equivalence
margins for all outcomes post-intervention.
These consistent findings are in agreement with previous research establishing the
safety of resistance exercise in regard to BCRL based on exercise prescription using low- to
moderate loads. The resistance exercise programs of previous work utilized loads corresponding to
60-80% 1 RM at 8-12 repetitions (59, 85) or started with little or no weight and slowly progressed
with the smallest weight increment possible until loads lifted corresponded to weights that
successfully could be lifted a minimum of 15 repetitions (86) or within a range of 10-12 repetitions
(87). Further our findings are in agreement with the results of two studies by Cormie et al. (13, 73),
demonstrating the safety of heavy-load resistance exercise in women with clinically stable BCRL
who had been diagnosed with breast cancer at least a year before study inclusion. These studies
found that the extent of arm swelling and associated BCRL symptoms remained stable immediately
post-, 24- and 72-hours after one bout of resistance exercise (73), and after twelve-weeks of regular
resistance exercise irrespective of low- or heavy-loads (75-85% of 1 RM using 6-10 RM) were
lifted (13). The results from the present thesis indicate that heavy-load resistance exercise,
specifically corresponding to 85-90% 1 RM at 5-8 repetitions, can be undertaken safely. Therefore,
the current evidence base (7, 8, 10, 11) can now be extended to include participation in heavy-load
resistance exercise.
52
Point prevalence
Post-intervention point prevalence rates were obtained in Studies 1 and 3 with variations depending
on the method of measurement (Tables 6 and 11). This is in accordance with previous studies
finding that applied diagnostic methods influences incidence and prevalence rates (4, 88) and
exemplifies the challenges in providing accurate estimates of BCRL. Importantly however, similar
point prevalence rates were observed between the HIGH and LOW group in Study 3 for any given
measurement method. Beyond measurement methods, other factors influence estimates of BCRL
prevalence including treatment burden (30) and timing of measurements post-surgery (4, 40)
limiting comparisons between studies. To the authors knowledge, the only meaningful comparison
is to a randomized controlled trial by Kilbreath et al. (n = 160) (66). This study evaluated eight
weeks of low to moderate load resistance exercise, starting 4-6 post-surgery, and found point
prevalent rates corresponding to 7% and 8% in the exercise group (rates were determined using BIS
and Circumference >2 cm, respectively) (66). While the Kilbreath study provides a relevant
comparison in regard to timing and measurement method, it should however be noted that over 95%
of the participants in Studies 1 and 3 were receiving adjuvant taxane-based chemotherapy. In
comparison about half (52.5%) of the participants in the Kilbreath study were receiving taxane-
based chemotherapy. This is relevant, as generalized edema and ensuing arm swelling is a known
side-effect to taxane-based chemotherapy. As such, our data estimating point prevalence of BCRL
following a multimodal exercise intervention including heavy-load resistance exercise provides
further evidence of the safety of this exercise modality.
Muscular strength
Significant post-intervention (p < 0.05) upper extremity strength increases were observed after six
weeks of participation in Body & Cancer (Study 1), and after twelve weeks in the HIGH
intervention (Study 3) (Tables 5 and 14). Further significant between group differences in strength
were observed with an increase of 13% in the HIGH group, compared to a 3% increase in the LOW
group. This is relevant as upper extremity strength in breast cancer survivors during cancer
treatment (without intervention) has been found to be 12-16% lower compared to healthy women
(89). Further, increases in upper extremity strength in the HIGH group corresponded to an effect
size of 0.55 (95% CI 0.35-0.70), similar to pooled estimates from a systematic review (8).
Specifically, fifteen randomized controlled trials evaluating populations with stable BCRL or at risk
for developing BCRL were included in the systematic review, finding that participation in
resistance exercise significantly increased muscular strength compared to controls with an effect
53
size 0.57 (95% CI 0.37-0.76). Therefore, the observed effect sizes after participation in the HIGH
intervention are encouraging, especially considering that none of the studies in the systematic
review exclusively included previously physically inactive breast cancer survivors receiving taxane-
based chemotherapy. As such, the present study indicates that participation in a multimodal
intervention incorporating heavy-load resistance exercise during chemotherapy can mitigate
declines in muscle strength.
Though no between group differences were observed for any subscale score of the
EORTC QLQ- B23 it should be highlighted that clinically relevant within group reductions in
breast and arm symptoms were found in the HIGH group (90) at both 6- and 12 weeks. These data
are similar to findings by the aforementioned studies of Kilbreath (66) and Cormie (13). Namely,
that clinically relevant reductions were observed post-intervention in both studies, despite no
statistically significant difference between exercise and control groups. Therefore, the data from the
present thesis provide additional evidence that participation in heavy-load resistance does not
precipitate BCRL, and likely alleviates breast and arm symptoms associated with breast cancer
surgery and treatment.
Methodological considerations
Internal validity
Measurement methods
No objective measures of BCRL were obtained in Study 1 with a self-reported clinician diagnosis
defined as a lymphedema case. Circumference measurements, taken at the time of diagnosis, were
however obtained for 38 (93%) of the women that reported a diagnosis of BCRL confirming BCRL
objectively. This measurement method is considered acceptable as a minimum standard provided
that measurements are obtained using a non-stretch tape measure at multiple points on each arm,
and is performed by health professionals with extensive training in this measurement method, in
order to provide reliable measures (39). As the circumference data in Study 1 were collected by
eight different clinicians using varying measurement protocols, circumference measurements
provided are not standardized and the level of training of the various clinicians is unknown.
Therefore, though the attainment of circumference measures adds strength to the study these
limitations should be taken into consideration. Nonetheless, these data reflect the reality of clinical
practice and provided a basis for Studies 2 and 3 where validated objective measurement methods
were used to assess presence and severity of lymphedema.
54
Measurement methods such as circumference, water displacement, and perometry are
limited in their ability to differentiate between tissue types and indirectly measure extracellular fluid
(approximately 25% of the total limb), by measuring the total volume of the entire extremity (67,
88). In contrast, BIS directly measures lymph fluid change by measuring the impedance to a low
level electrical current. This allows for a sensitive (74, 91) and reliable measurement method for
detecting subclinical BCRL (91) (early BCRL characterized by an increase in extracellular fluid).
Further, as impedance values are converted to an L-Dex score, inherent volume differences
associated with hand dominance are taken into account (88, 91). However, as lymphedema
progresses BIS loses its sensitivity as extracellular fluid is replaced with fibrotic and adipose
tissues, and is therefore not considered an appropriate measurement method to monitor BCRL over
time (74, 88). However, as the purpose of Studies 2 and 3 were to detect changes in extracellular
fluid in women at risk for BCRL, the BIS measurements add strength to the results.
DXA provides a sensitive measure of tissue composition using a three-compartment
model providing estimates of bone mass composition, fat mass and lean mass where the lean mass
component includes extracellular fluid (71, 74, 75). DXA is sensitive to changes in tissue
composition, and is therefore able to monitor BCRL over time as fluid components are replaced
with adipose tissue. Further, DXA allows for analysis of separate regions of the arm, of potential
clinical importance for patients where swelling is confined to a specific region of the arm or hand
(71, 74, 75, 92). Two different DXA scan and analysis protocols were used in this thesis. In study 2,
separate arm scans were performed and software with a high resolution was used as described by
Gjorup et al., (71), allowing for more precise definition of the region of interest and correct
definition of bone and soft tissue. In study 3, whole body scans were performed and analyzed with
standard total body software (74, 75). However, due to body dimensions exceeding the scan area,
28% of the sample (n = 42) are missing inter-arm volume data, why caution should be applied when
generalizing Study 3 findings to obese women, and is a limitation to this protocol. As an alternative
for these individuals, the potential of performing separate arms scans exists.
In line with existing recommendations advocating for subjective symptom assessment
alongside objective measurements (39), breast and arm symptoms were monitored using a validated
questionnaire (EORTC QLQ-BR23) in Study 3, as well as the severity of swelling, heaviness, pain
and tightness using a numeric rating scale (72, 73) in Study 2 and 3. This is relevant as breast
cancer survivors at risk for lymphedema may experience a variety of symptoms, which can be the
earliest indicator of an ensuing BCRL (93). Further, assessment of symptoms provides a more
55
comprehensive evaluation of BCRL that takes the participant’s perceptions into consideration,
which arguably is more important than any objective measurement. Finally, as complete BIS and
DXA data were not available in Study 3, the self-report measures ensured that 100% data for at
least one outcome was available adding strength to the findings.
Blinding
Inherent to exercise intervention studies, Studies 2 and 3 were not double-blinded. However,
considerable effort was made to reduce the potential of assessor bias as data was collected blinded
by medical technicians and study assessors with no knowledge of group allocation. Further,
outcomes were obtained objectively and assessors followed detailed protocols, with previous test
results concealed at follow-up assessments so that neither the participant nor the assessor knew their
previous scores. Keying of data and statistical analyses were also performed blinded to group
allocation.
Equivalence margins
As it was hypothesized that lymphatic response would be similar between groups in Study 2 and 3,
the equivalence design was considered the most appropriate analysis of BCRL outcomes. This was
formalized by defining equivalence margins for each outcome, which ideally represent the
maximum clinically acceptable difference that one is willing to accept in return for the secondary
benefits of a new therapy (heavy-load resistance exercise) (81). The value and impact of
establishing equivalence depends on how well the equivalence margin can be justified in terms of
relevant evidence and clinical judgement, where a narrower equivalence margin makes it more
difficult to establish equivalence (81). This is exemplified by equivalence margins for L-Dex being
set at ± 3.0 in Study 2 rendering conclusions of nonequivalence between heavy- and low-loads at 72
hours. A priori, this threshold was chosen based on change scores considered to be clinically
relevant for persons with BCRL, as no known normative change scores existed for persons without
BCRL. However, in the interim to Study 3, normative L-Dex data were published indicating that L-
Dex scores fluctuate between 9-11 units, (70) which is why equivalence margins were set at ±5.0.
As such, equivalence would have been declared at all time points in Study 2 and illustrates the
challenges in defining meaningful margins in equivalence trials. The chosen equivalence margins in
Studies 2 and 3 were purposely set as more conservative (narrower) in order to ensure credibility.
Arguably though, this may have created confidence limits with an unnecessarily narrow interval
rendering conclusions of nonequivalence. While this may not be the case due to over-conservative
equivalence margins, the negative deviations favoring the Heavy-load or HIGH group add
56
confidence to the overall conclusion, that heavy-load resistance exercise does not exacerbate the
development of BCRL acutely or after twelve weeks of repeated exposure.
Follow-up data
39 weeks follow-up data were collected in Study 3, with findings indicating that the longer term
effect of the LOW and HIGH intervention was similar between groups or indicated reductions
favouring the HIGH group. These findings were consistent with the per-protocol analysis, with the
exception of L-Dex and pain as upper CIs indicated a slight increase beyond the predetermined
equivalence margin. However, in general, care should be taken when interpreting the 39 week
follow-up results as no data regarding upper extremity resistance exercise behaviour was collected
post-intervention. Consequently, we cannot determine whether effects seen at 39 weeks were a
result of resistance exercise or other unknown factors and is an additional limitation of this study.
External validity
When generalizing the results of the thesis to the larger breast cancer population at risk for
lymphedema a number of issues should be considered.
In Study 2, five women were excluded at baseline screening if they presented with evidence of
BCRL according to standardized protocols for BIS (L-Dex > 10) or visual inspection (CTC v3.0).
These women could however have been experiencing transient swelling. Further, though
participants were not screened for BCRL and excluded before participation in Studies 1 and 3,
transient cases were not specifically addressed. As such, the findings of this thesis do not extend to
breast cancer survivors displaying increased levels of extracellular fluid, but who have not been
diagnosed with- or received treatment for BCRL. Clinically, this is important as uncertainty exists
as to whether these women would respond in a positive or negative way to heavy-load resistance
exercise. Indeed, though previous studies have found resistance exercise, including heavy-load, to
be both safe and beneficial for breast cancer survivors with lymphedema, these studies have
included women presenting with a clinical diagnosis of BCRL (94) or specifically diagnosed stable
BCRL (e.g. no treatment within the last three months)(7, 8, 95, 96). Therefore, a paucity in
knowledge remains as to the appropriate resistance exercise prescription for women presenting with
potentially transient, unstable lymphedema.
Another limitation to this thesis was that participants making up our sample were on
average younger than women diagnosed with breast cancer. Further, inherent to exercise studies,
there may also have been a selection bias towards women motivated to exercise. Nonetheless, 60%
57
of the total cohort (n =194 (n = 41 Study 1, n =153 Study 3)) reported that they were physically
inactive pre- diagnosis which extends generalizability to this vulnerable groups. This is relevant as
fear of lymphedema has been identified as a barrier for physical activity, and especially vigorous or
strength activities (2), which in turn may lead to avoidance and non-adoption of regular physical
activity further increasing risk of BCRL (4). Also, recent work has found that attitude towards
exercise can be transformed from having no priority to being highly prioritized if support to adopt
exercise is received in physically inactive breast cancer survivors during adjuvant chemotherapy
(97). While it is not known whether this translates to long-term behavioral change, the potential for
long term adoption of exercise exists, ultimately leading to better health outcomes (98, 99).
Further, 96% (311) of the participants involved with Study 1, 2 or 3 were receiving
taxane-based adjuvant chemotherapy. As such, findings from this body of work are highly
generalizable to the majority of breast cancer survivors receiving adjuvant chemotherapy as taxane-
based chemotherapy is considered standard first line treatment (16, 100). Further, when considering
other evidence-based risk factors for developing BCRL, participants had an average BMI of 25, 172
(53%) had ALND, and 138 (43%) had undergone a mastectomy. Therefore, as multiple risk factors
for developing BCRL are well represented, applicability extends to breast cancer survivors at
additional risk for developing lymphedema.
Conclusion and clinical implications
In conclusion, across studies, we found no evidence to suggest that participating in heavy-load
resistance exercise during adjuvant taxane-based chemotherapy for breast cancer increased the risk
of developing BCRL. Further, benefits were observed in upper extremity strength, as well as
clinically relevant reductions in breast cancer-specific arm and breast symptoms related to
participation in a multimodal exercise intervention including heavy-load resistance exercise.
Importantly, as this thesis targeted breast cancer survivors with multiple risk factors for developing
BCRL (axillary surgery, physically inactive, taxane-based chemotherapy), applicability extends to
those considered at high-risk for developing BCRL. Therefore, breast cancer survivors should be
encouraged to adopt exercise including heavy-load resistance exercise without fear of exacerbating
BCRL development during adjuvant chemotherapy and beyond.
Breast cancer survivors commonly receive risk reduction advice cautioning against
heavy lifting (2, 46) despite revisions from the National Lymphedema Network, omitting this
particular risk reduction strategy (9). Findings from the present thesis lend clinical evidence that
58
supports these revisions, as we found no evidence indicating that intermittent activities of daily
living including heavy-load lifting need be avoided. These results are in accordance with previous
research finding that unrestricted activity of the upper extremities did not alter BCRL risk (86).
Further, Round et al. found that the best functional outcomes were found in those who followed
minimal activity restrictions and used their at-risk extremity as much as the contralateral extremity
(101). As such, breast cancer survivors should be encouraged, without restrictions, to participate in
activities of daily living in accordance with signs and symptoms of BCRL.
Perspectives and future research
The findings from this thesis are in support of current lymphedema risk reduction recommendations
from The National Comprehensive Cancer Network and The American Society of Breast Surgeons (39).
These recommendations advocate for patient education which encourages participation in regular exercise
(without restrictions) and weight management, while also providing information about early signs and
symptoms of BCRL (e.g. tightness, heaviness and swelling) and individual lifetime risk for developing
BCRL. This is relevant as early self-detection combined with prompt intervention has been associated with
better outcomes (102). Indeed, a paradigm shift in BCRL surveillance has occurred with increasing support
for early-detection strategies whereby reversible stages of lymphedema (stage 0 -1) are identified.
Identifying subclinical lymphedema facilitates early, less time consuming and less cumbersome intervention
(e.g. compression garment, self-care, self-MLD) which likely reduces BCRL progression and is likely more
cost-effective than waiting for obvious swelling to occur (22, 103). Various prospective surveillance models
have been proposed to facilitate early detection. However, consensus is lacking with regard to the optimal
frequency and duration of surveillance, and with respect to who should be regularly surveyed (102). Further,
the detection of subclinical lymphedema has in large part been made possible due to the increased sensitivity
of measurement methods such as BIS and perometry, as well as tissue dielectric constant and DXA.
However, agreement as to the optimal measurement method or methods is lacking as advantages and
disadvantages exist for each of these diagnostic tools (102).Therefore, though current data supports the
implementation of prospective surveillance (102), future work should provide prospective comparisons of
measurement methods and current prospective models with long-term follow-up and cost-benefit analyses in
order to elucidate the best early detection strategy (or strategies).
A considerable rationale exists for participating in resistance exercise during adjuvant
chemotherapy as previous clinical trials using low to moderate loads have found that resistance
exercise elicits gains in muscle strength while mitigating adverse changes in physical components
of quality of life, including fatigue, without increased risk of BCRL (7, 8, 10, 11, 54). Moreover, it
has been hypothesized that resistance exercise reduces taxane-related edema through the effects of
59
the muscle pump (33, 40). Due to the dose-response relationship that exists between loads lifted and
gains in muscular structure and function it is feasible that additional benefits can be gained. Further
it is plausible that participation in heavy-load resistance exercise may instigate more effective
lymphatic function change than low-load resistance exercise, and in doing so, potentially have a
greater effect on reducing BCRL risk. Therefore, a head to head comparison between resistance
exercise loads should be undertaken with results from this thesis providing the necessary evidence
to carry out this work.
60
References
1. Engholm G FJ, Christensen N, Kejs AMT, Hertzum-Larsen R, Johannesen TB, Khan S, Leinonen MK, Ólafsdóttir E, Petersen T, Schmidt LKH, Trykker H, Storm HH. NORDCAN: Cancer Incidence, Mortality, Prevalence and Survival in the Nordic Countries,Version 7.3: Association of the Nordic Cancer Registries. Danish Cancer Society 2014 [updated 08.07.2016; cited 2017 22/10/2017]. Available from: http://www.ancr.nu. 2. Sander AP, Wilson J, Izzo N, Mountford SA, Hayes KW. Factors that affect decisions about physical activity and exercise in survivors of breast cancer: a qualitative study. Phys Ther. 2012;92(4):525-36. 3. Binkley JM, Harris SR, Levangie PK, Pearl M, Guglielmino J, Kraus V, Rowden D. Patient perspectives on breast cancer treatment side effects and the prospective surveillance model for physical rehabilitation for women with breast cancer. Cancer. 2012;118(8 Suppl):2207-16. 4. DiSipio T, Rye S, Newman B, Hayes S. Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis. Lancet Oncol. 2013;14(6):500-15. 5. Stanton AW, Modi S, Mellor RH, Levick JR, Mortimer PS. Recent advances in breast cancer-related lymphedema of the arm: lymphatic pump failure and predisposing factors. Lymphat Res Biol. 2009;7(1):29-45. 6. Cintolesi V, Stanton AW, Bains SK, Cousins E, Peters AM, Purushotham AD, Levick JR, Mortimer PS. Constitutively Enhanced Lymphatic Pumping in the Upper Limbs of Women Who Later Develop Breast Cancer-Related Lymphedema. Lymphat Res Biol. 2016;14(2):50-61. 7. Paramanandam VS, Roberts D. Weight training is not harmful for women with breast cancer-related lymphoedema: a systematic review. J Physiother. 2014;60(3):136-43. 8. Cheema BS, Kilbreath SL, Fahey PP, Delaney GP, Atlantis E. Safety and efficacy of progressive resistance training in breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat. 2014;148(2):249-68. 9. Schmitz KH. Balancing lymphedema risk: exercise versus deconditioning for breast cancer survivors. Exerc Sport Sci Rev. 2010;38:17-24. 10. Keilani M, Hasenoehrl T, Neubauer M, Crevenna R. Resistance exercise and secondary lymphedema in breast cancer survivors-a systematic review. Support Care Cancer. 2016;24(4):1907-16. 11. Nelson NL. Breast Cancer-Related Lymphedema and Resistance Exercise: A Systematic Review. J Strength Cond Res. 2016;30(9):2656-65. 12. Cormie P, Galvao DA, Spry N, Newton RU. Neither heavy nor light load resistance exercise acutely exacerbates lymphedema in breast cancer survivor. Integr Cancer Ther. 2013;12(5):423-32. 13. Cormie P, Pumpa K, Galvao DA, Turner E, Spry N, Saunders C, Zissiadis Y, Newton RU. Is it safe and efficacious for women with lymphedema secondary to breast cancer to lift heavy weights during exercise: a randomised controlled trial. J Cancer Surviv. 2013;7(3):413-24. 14. International Agency for research on Cancer WHO. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence in 2012 [cited 2017 August 28]. Available from: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. 15. Sundhedsdatastyrelsen. Nye Kræfttilfælde i Danmark, Cancerregisteret 2015 2016 [cited 2017 18 August]. Available from: https://sundhedsdatastyrelsen.dk/da/tal-og-analyser/analyser-og-rapporter/sygdomme/cancerregisteret. 16. Group DBCC. Danish Breast Cancer Coopertive Group; Retningslinjer Medicinsk Behandling 2017 [updated April 2017; cited 2017 28. november]. Available from: http://www.dbcg.dk/PDF%20Filer/Kap_6_Medicinsk_behandling-07.04.2017.pdf. 17. Gho SA, Steele JR, Jones SC, Munro BJ. Self-reported side effects of breast cancer treatment: a cross-sectional study of incidence, associations, and the influence of exercise. Cancer Causes Control. 2013;24(3):517-28.
61
18. Hayes SC, Johansson K, Stout NL, Prosnitz R, Armer JM, Gabram S, Schmitz KH. Upper-body morbidity after breast cancer: incidence and evidence for evaluation, prevention, and management within a prospective surveillance model of care. Cancer. 2012;118(8 Suppl):2237-49. 19. Ewertz M, Jensen AB. Late effects of breast cancer treatment and potentials for rehabilitation. Acta Oncol. 2011;50(2):187-93. 20. Cheville AL, McGarvey CL, Petrek JA, Russo SA, Thiadens SR, Taylor ME. The grading of lymphedema in oncology clinical trials. Semin Radiat Oncol. 2003;13(3):214-25. 21. Mortimer PS, Rockson SG. New developments in clinical aspects of lymphatic disease. J Clin Invest. 2014;124(3):915-21. 22. The International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2016 consensus document of the International Society of Lymphology. Lymphology. 2016;49:170-84. 23. Smile TD, Tendulkar R, Schwarz G, Arthur D, Grobmyer S, Valente S, Vicini F, Shah C. A Review of Treatment for Breast Cancer-Related Lymphedema: Paradigms for Clinical Practice. Am J Clin Oncol. 2016:Epub ahead of print. 24. Morgan PA, Franks PJ, Moffatt CJ. Health-related quality of life with lymphoedema: a review of the literature. Int Wound J. 2005;2(1):47-62. 25. Fu MR, Ridner SH, Hu SH, Stewart BR, Cormier JN, Armer JM. Psychosocial impact of lymphedema: a systematic review of literature from 2004 to 2011. Psychooncology. 2013;22(7):1466-84. 26. Johansson K, Holmstrom H, Nilsson I, Ingvar C, Albertsson M, Ekdahl C. Breast cancer patients' experiences of lymphoedema. Scand J Caring Sci. 2003;17(1):35-42. 27. Vassard D, Olsen MH, Zinckernagel L, Vibe-Petersen J, Dalton SO, Johansen C. Psychological consequences of lymphoedema associated with breast cancer: a prospective cohort study. Eur J Cancer. 2010;46(18):3211-8. 28. Boyages J, Kalfa S, Xu Y, Koelmeyer L, Mackie H, Viveros H, Taksa L, Gollan P. Worse and worse off: the impact of lymphedema on work and career after breast cancer. Springerplus. 2016;5:657. 29. Ahmed RL, Prizment A, Lazovich D, Schmitz KH, Folsom AR. Lymphedema and quality of life in breast cancer survivors: the Iowa Women's Health Study. J Clin Oncol. 2008;26(35):5689-96. 30. Gartner R, Jensen MB, Kronborg L, Ewertz M, Kehlet H, Kroman N. Self-reported arm-lymphedema and functional impairment after breast cancer treatment--a nationwide study of prevalence and associated factors. Breast. 2010;19(6):506-15. 31. Kræftens Bekæmpelse. En kortlægning af lymfødem i relation til kræft- Epidemiologi, organisering af behandlingstilbud of erfaringer fra Norge og Sverige 2016 [cited 2017 November]. Available from: https://www.cancer.dk/dyn/resources/File/file/9/6259/1490952601/lymfoedem-rapport_final_feb-2017.pdf. 32. Bulley C CF, Blyth C, Jack W, Chetty MU, Barber M, Tan CW. Prevalence and Impacts of Upper Limb Morbidity after Treatment for Breast Cancer: A Cross-Sectional Study of Lymphedema and Function. Canc Oncol Res. 2013;1(2):30-9. 33. Lane K, Worsley D, McKenzie D. Exercise and the lymphatic system: implications for breast-cancer survivors. Sports Med. 2005;35(6):461-71. 34. Morrow M, Van Zee KJ, Patil S, Petruolo O, Mamtani A, Barrio AV, Capko D, El-Tamer M, Gemignani ML, Heerdt AS, Kirstein L, Pilewskie M, Plitas G, Sacchini VS, Sclafani LM, Ho A, Cody HS. Axillary Dissection and Nodal Irradiation Can Be Avoided for Most Node-positive Z0011-eligible Breast Cancers: A Prospective Validation Study of 793 Patients. Ann Surg. 2017;266(3):457-62. 35. Group DBC. Anvendelse af sentinel node biopsi 2013 [updated 2013; cited 2018. Available from: http://www.dbcg.dk/PDF%20Filer/Kap_12_Anvendelse_af_sentinel_node_06.02.13.pdf. 36. Gartner R, Mejdahl MK, Andersen KG, Ewertz M, Kroman N. Development in self-reported arm-lymphedema in Danish women treated for early-stage breast cancer in 2005 and 2006--a nationwide follow-up study. Breast. 2014;23(4):445-52.
62
37. Norman SA, Localio AR, Potashnik SL, Simoes Torpey HA, Kallan MJ, Weber AL, Miller LT, Demichele A, Solin LJ. Lymphedema in breast cancer survivors: incidence, degree, time course, treatment, and symptoms. J Clin Oncol. 2009;27(3):390-7. 38. Smile TD, Tendulkar R, Schwarz G, Arthur D, Grobmyer S, Valente S, Vicini F, Shah C. A Review of Treatment for Breast Cancer-Related Lymphedema: Paradigms for Clinical Practice. Am J Clin Oncol. 2016. 39. McLaughlin SA, Staley AC, Vicini F, Thiruchelvam P, Hutchison NA, Mendez J, MacNeill F, Rockson SG, DeSnyder SM, Klimberg S, Alatriste M, Boccardo F, Smith ML, Feldman SM. Considerations for Clinicians in the Diagnosis, Prevention, and Treatment of Breast Cancer-Related Lymphedema: Recommendations from a Multidisciplinary Expert ASBrS Panel : Part 1: Definitions, Assessments, Education, and Future Directions. Ann Surg Oncol. 2017;24(10):2818-26. 40. Kilbreath SL, Lee MJ, Refshauge KM, Beith JM, Ward LC, Simpson JM, Black D. Transient swelling versus lymphoedema in the first year following surgery for breast cancer. Support Care Cancer. 2013;21(8):2207-15. 41. Kilbreath SL, Refshauge KM, Beith JM, Ward LC, Ung OA, Dylke ES, French JR, Yee J, Koelmeyer L, Gaitatzis K. Risk factors for lymphoedema in women with breast cancer: A large prospective cohort. Breast. 2016;28:29-36. 42. McLaughlin SA, DeSnyder SM, Klimberg S, Alatriste M, Boccardo F, Smith ML, Staley AC, Thiruchelvam PTR, Hutchison NA, Mendez J, MacNeill F, Vicini F, Rockson SG, Feldman SM. Considerations for Clinicians in the Diagnosis, Prevention, and Treatment of Breast Cancer-Related Lymphedema, Recommendations from an Expert Panel: Part 2: Preventive and Therapeutic Options. Ann Surg Oncol. 2017;24(10):2827-35. 43. Toyserkani NM, Jensen CH, Andersen DC, Sheikh SP, Sorensen JA. Treatment of Breast Cancer-Related Lymphedema with Adipose-Derived Regenerative Cells and Fat Grafts: A Feasibility and Safety Study. Stem Cells Transl Med. 2017;6(8):1666-72. 44. Committee NLNMA. Position statement of the National Lymphedema Network 2012 [updated May 2012; cited 2017 October 8]. Available from: https://www.lymphnet.org/pdfDocs/nlnriskreduction.pdf. 45. Asdourian MS, Skolny MN, Brunelle C, Seward CE, Salama L, Taghian AG. Precautions for breast cancer-related lymphoedema: risk from air travel, ipsilateral arm blood pressure measurements, skin puncture, extreme temperatures, and cellulitis. Lancet Oncol. 2016;17(9):e392-405. 46. McLaughlin SA, Bagaria S, Gibson T, Arnold M, Diehl N, Crook J, Parker A, Nguyen J. Trends in risk reduction practices for the prevention of lymphedema in the first 12 months after breast cancer surgery. J Am Coll Surg. 2013;216(3):380-9; quiz 511-3. 47. Egan B, Zierath JR. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab. 2013;17(2):162-84. 48. Csapo R, Alegre LM. Effects of resistance training with moderate vs heavy loads on muscle mass and strength in the elderly: A meta-analysis. Scand J Med Sci Sports. 2016;26(9):995-1006. 49. Christensen JF, Jones LW, Andersen JL, Daugaard G, Rorth M, Hojman P. Muscle dysfunction in cancer patients. Ann Oncol. 2014;25(5):947-58. 50. American College of Sports Medicine position stand. Progression models in resistance training for healthy adults. Med Sci Sports Exerc. 2009;41(3):687-708. 51. Levinger I, Goodman C, Hare DL, Jerums G, Toia D, Selig S. The reliability of the 1RM strength test for untrained middle-aged individuals. J Sci Med Sport. 2009;12(2):310-6. 52. Kohrt WM, Bloomfield SA, Little KD, Nelson ME, Yingling VR. American College of Sports Medicine Position Stand: physical activity and bone health. Med Sci Sports Exerc. 2004;36(11):1985-96. 53. Brown JC, Huedo-Medina TB, Pescatello LS, Pescatello SM, Ferrer RA, Johnson BT. Efficacy of exercise interventions in modulating cancer-related fatigue among adult cancer survivors: a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2011;20(1):123-33.
63
54. Schmidt ME, Wiskemann J, Armbrust P, Schneeweiss A, Ulrich CM, Steindorf K. Effects of resistance exercise on fatigue and quality of life in breast cancer patients undergoing adjuvant chemotherapy: A randomized controlled trial. Int J Cancer. 2015;137(2):471-80. 55. Demark-Wahnefried W, Campbell KL, Hayes SC. Weight management and its role in breast cancer rehabilitation. Cancer. 2012;118(8 Suppl):2277-87. 56. Harrison S, Hayes SC, Newman B. Level of physical activity and characteristics associated with change following breast cancer diagnosis and treatment. Psychooncology. 2009;18(4):387-94. 57. Irwin ML, Crumley D, McTiernan A, Bernstein L, Baumgartner R, Gilliland FD, Kriska A, Ballard-Barbash R. Physical activity levels before and after a diagnosis of breast carcinoma: the Health, Eating, Activity, and Lifestyle (HEAL) study. Cancer. 2003;97(7):1746-57. 58. Stenholm S, Harris TB, Rantanen T, Visser M, Kritchevsky SB, Ferrucci L. Sarcopenic obesity: definition, cause and consequences. Curr Opin Clin Nutr Metab Care. 2008;11(6):693-700. 59. Courneya KS, Segal RJ, Mackey JR, Gelmon K, Reid RD, Friedenreich CM, Ladha AB, Proulx C, Vallance JK, Lane K, Yasui Y, McKenzie DC. Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial. J Clin Oncol. 2007;25(28):4396-404. 60. Swaroop MN, Ferguson CM, Horick NK, Skolny MN, Miller CL, Jammallo LS, Brunelle CL, O'Toole JA, Isakoff SJ, Specht MC, Taghian AG. Impact of adjuvant taxane-based chemotherapy on development of breast cancer-related lymphedema: results from a large prospective cohort. Breast Cancer Res Treat. 2015;151(2):393-403. 61. Adamsen L, Quist M, Andersen C, Moller T, Herrstedt J, Kronborg D, Baadsgaard MT, Vistisen K, Midtgaard J, Christiansen B, Stage M, Kronborg MT, Rorth M. Effect of a multimodal high intensity exercise intervention in cancer patients undergoing chemotherapy: randomised controlled trial. BMJ. 2009;339:b3410. 62. Altman DG. Practical Statistics for Medical Research. London: Chapman & Hall/CRC; 1991. 624 p. 63. Danish Health and Medical Authority. Physical activity: recommendations for adults (18-64 years old) 2013 [cited 2017 Nov]. Available from: http://www.sst.dk/English/Health_promotion/Physical_activity/Recommendations_for_adults.aspx. 64. Moller T, Lillelund C, Andersen C, Ejlertsen B, Norgaard L, Christensen KB, Vadstrup E, Diderichsen F, Hendriksen C, Bloomquist K, Adamsen L. At cancer diagnosis: a 'window of opportunity' for behavioural change towards physical activity. A randomised feasibility study in patients with colon and breast cancer. BMJ Open. 2013;3(11):e003556. 65. Saltin B, Grimby G. Physiological analysis of middle-aged and old former athletes. Comparison with still active athletes of the same ages. Circulation. 1968;38(6):1104-15. 66. Kilbreath SL, Refshauge KM, Beith JM, Ward LC, Lee M, Simpson JM, Hansen R. Upper limb progressive resistance training and stretching exercises following surgery for early breast cancer: a randomized controlled trial. Breast Cancer Res Treat. 2012;133(2):667-76. 67. Cornish BH, Thomas BJ, Ward LC, Hirst C, Bunce IH. A new technique for the quantification of peripheral edema with application in both unilateral and bilateral cases. Angiology. 2002;53(1):41-7. 68. Ward LC, Dylke E, Czerniec S, Isenring E, Kilbreath SL. Confirmation of the reference impedance ratios used for assessment of breast cancer-related lymphedema by bioelectrical impedance spectroscopy. Lymphat Res Biol. 2011;9(1):47-51. 69. Cornish BH, Jacobs A, Thomas BJ, Ward LC. Optimizing electrode sites for segmental bioimpedance measurements. Physiol Meas. 1999;20(3):241-50. 70. Hayes S, Janda M, Steele M, et al. Identifying diagnostic criteria for upper- and lower-limb lymphoedema Impedimed Limited: Queensland University of Technology Faculty of Health, School of Public Health and Social Work and Institute of Health and Biomedical Innovation; 2016 [updated 3 July 2017; cited 2017 July 3]. 17]. Available from: https://eprints.qut.edu.au/view/person/Hayes,_Sandra.html#group_report.
64
71. Gjorup C, Zerahn B, Hendel HW. Assessment of volume measurement of breast cancer-related lymphedema by three methods: circumference measurement, water displacement, and dual energy X-ray absorptiometry. Lymphat Res Biol. 2010;8(2):111-9. 72. Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken). 2011;63 Suppl 11:S240-52. 73. Cormie P, Galvao DA, Spry N, Newton RU. Neither heavy nor light load resistance exercise acutely exacerbates lymphedema in breast cancer survivors. Integr Cancer Ther. 2013;12(5):423-32. 74. Newman AL, Rosenthall L, Towers A, Hodgson P, Shay CA, Tidhar D, Vigano A, Kilgour RD. Determining the precision of dual energy x-ray absorptiometry and bioelectric impedance spectroscopy in the assessment of breast cancer-related lymphedema. Lymphat Res Biol. 2013;11(2):104-9. 75. Brorson H, Ohlin K, Olsson G, Karlsson MK. Breast cancer-related chronic arm lymphedema is associated with excess adipose and muscle tissue. Lymphat Res Biol. 2009;7(1):3-10. 76. Sprangers MA, Groenvold M, Arraras JI, Franklin J, te Velde A, Muller M, Franzini L, Williams A, de Haes HC, Hopwood P, Cull A, Aaronson NK. The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study. J Clin Oncol. 1996;14(10):2756-68. 77. Nguyen J, Popovic M, Chow E, Cella D, Beaumont JL, Chu D, DiGiovanni J, Lam H, Pulenzas N, Bottomley A. EORTC QLQ-BR23 and FACT-B for the assessment of quality of life in patients with breast cancer: a literature review. J Comp Eff Res. 2015;4(2):157-66. 78. Liang K-Y, & Zeger, S.L. Longitudinal data analysis using generalized linear models. Biometrika. 1986;73:13-22. 79. Stout Gergich NL, Pfalzer LA, McGarvey C, Springer B, Gerber LH, Soballe P. Preoperative assessment enables the early diagnosis and successful treatment of lymphedema. Cancer. 2008;112(12):2809-19. 80. Westlake WJ. Use of confidence intervals in analysis of comparative bioavailability trials. J Pharm Sci. 1972;61(8):1340-1. 81. Walker E, Nowacki AS. Understanding equivalence and noninferiority testing. J Gen Intern Med. 2011;26(2):192-6. 82. Team RC. R: A language and environment for statistical computing.: R Foundation for Statistical Computing; 2015 [Available from: https://www.R-project.org/. 83. Halekoh U HS, Yan J. The R package geepack for generalized estimatin equations. J Stat Softw. 2006;15(2):1-11. 84. Cohen J. Statistical power analysis for the behavioral sciences. Second ed: Academic press; 1977. 85. Simonavice E, Kim JS, Panton L. Effects of resistance exercise in women with or at risk for breast cancer-related lymphedema. Support Care Cancer. 2017;25(1):9-15. 86. Sagen A, Karesen R, Risberg MA. Physical activity for the affected limb and arm lymphedema after breast cancer surgery. A prospective, randomized controlled trial with two years follow-up. Acta Oncol. 2009;48(8):1102-10. 87. Schmitz KH, Ahmed RL, Troxel AB, Cheville A, Lewis-Grant L, Smith R, Bryan CJ, Williams-Smith CT, Chittams J. Weight lifting for women at risk for breast cancer-related lymphedema: a randomized trial. JAMA. 2010;304(24):2699-705. 88. Hayes SC, Speck RM, Reimet E, Stark A, Schmitz KH. Does the effect of weight lifting on lymphedema following breast cancer differ by diagnostic method: results from a randomized controlled trial. Breast Cancer Res Treat. 2011;130(1):227-34.
65
89. Klassen O, Schmidt ME, Ulrich CM, Schneeweiss A, Potthoff K, Steindorf K, Wiskemann J. Muscle strength in breast cancer patients receiving different treatment regimes. J Cachexia Sarcopenia Muscle. 2017;8(2):305-16. 90. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol. 1998;16(1):139-44. 91. Fu MR, Cleland CM, Guth AA, Kayal M, Haber J, Cartwright F, Kleinman R, Kang Y, Scagliola J, Axelrod D. L-dex ratio in detecting breast cancer-related lymphedema: reliability, sensitivity, and specificity. Lymphology. 2013;46(2):85-96. 92. Czerniec SA, Ward LC, Meerkin JD, Kilbreath SL. Assessment of segmental arm soft tissue composition in breast cancer-related lymphedema: a pilot study using dual energy X-ray absorptiometry and bioimpedance spectroscopy. Lymphat Res Biol. 2015;13(1):33-9. 93. Fu MR, Axelrod D, Cleland CM, Qiu Z, Guth AA, Kleinman R, Scagliola J, Haber J. Symptom report in detecting breast cancer-related lymphedema. Breast Cancer (Dove Med Press). 2015;7:345-52. 94. Hayes SC, Reul-Hirche H, Turner J. Exercise and secondary lymphedema: safety, potential benefits, and research issues. Med Sci Sports Exerc. 2009;41(3):483-9. 95. Schmitz KH, Ahmed RL, Troxel A, Cheville A, Smith R, Lewis-Grant L, Bryan CJ, Williams-Smith CT, Greene QP. Weight lifting in women with breast-cancer-related lymphedema. N Engl J Med. 2009;361(7):664-73. 96. Buchan J, Janda M, Box R, Schmitz K, Hayes S. A Randomized Trial on the Effect of Exercise Mode on Breast Cancer-Related Lymphedema. Med Sci Sports Exerc. 2016;48(10):1866-74. 97. Adamsen L, Andersen C, Lillelund C, Bloomquist K, Moller T. Rethinking exercise identity: a qualitative study of physically inactive cancer patients' transforming process while undergoing chemotherapy. BMJ Open. 2017;7(8):e016689. 98. Holmes MD, Chen WY, Feskanich D, Kroenke CH, Colditz GA. Physical activity and survival after breast cancer diagnosis. JAMA. 2005;293(20):2479-86. 99. Fong DY, Ho JW, Hui BP, Lee AM, Macfarlane DJ, Leung SS, Cerin E, Chan WY, Leung IP, Lam SH, Taylor AJ, Cheng KK. Physical activity for cancer survivors: meta-analysis of randomised controlled trials. BMJ. 2012;344:e70. 100. Giordano SH, Lin YL, Kuo YF, Hortobagyi GN, Goodwin JS. Decline in the use of anthracyclines for breast cancer. J Clin Oncol. 2012;30(18):2232-9. 101. Round T, Hayes SC, Newman B. How do recovery advice and behavioural characteristics influence upper-body function and quality of life among women 6 months after breast cancer diagnosis? Support Care Cancer. 2006;14(1):22-9. 102. Shah C, Arthur DW, Wazer D, Khan A, Ridner S, Vicini F. The impact of early detection and intervention of breast cancer-related lymphedema: a systematic review. Cancer Med. 2016;5(6):1154-62. 103. Stout NL, Pfalzer LA, Springer B, Levy E, McGarvey CL, Danoff JV, Gerber LH, Soballe PW. Breast cancer-related lymphedema: comparing direct costs of a prospective surveillance model and a traditional model of care. Phys Ther. 2012;92(1):152-63.
66
Appendices
Appendix A: Papers I to IV
Appendix B: Co-authorship declarations
Appendix C: Study 1
Telephone interview guide
Appendix D: Study 3
EORTC- BR23
BCRL information
Subjective BCRL outcomes structured interview
Appendix A: Papers I to IV
Paper I
Correspondence: K. Bloomquist, University Hospitals Centre for Health Research, Copenhagen University Hospital, 2100 Copenhagen, Denmark. Tel: � 45 35457336. Fax: � 45 35457399. E-mail: [email protected]
(Received 14 June 2013 ; accepted 26 August 2013 )
ORIGINAL ARTICLE
Heavy resistance training and lymphedema: Prevalence of breast cancer-related lymphedema in participants of an exercise intervention utilizing heavy load resistance training
KIRA BLOOMQUIST 1 , TONNY KARLSMARK 2 , KARL BANG CHRISTENSEN 3 & LIS ADAMSEN 1,4
1 University Hospitals Centre for Health Research, Copenhagen University Hospital, Copenhagen, Denmark, 2 Department of Dermatology and Venerology, Bispebjerg Hospital, University Hospital of Copenhagen, Denmark, 3 Department of Public Health, Section of Biostatistics, University of Copenhagen, Denmark and 4 Department of Public Health, University of Copenhagen, Denmark
Abstract Background. There is limited knowledge regarding progressive resistance training during adjuvant chemotherapy and the risk of developing breast cancer-related lymphedema (BCRL). Furthermore, no studies have investigated the safety of resistance training with heavy loads ( � 80% 1 repetition maximum) in this population. ‘ Body and Cancer ’ is a six-week, nine-hour weekly, supervised, multimodal exercise intervention utilizing progressive resistance training with heavy loads for cancer patients undergoing chemotherapy. The purpose of the present study was to estimate the prevalence of BCRL in former participants, and identify associations between progressive resistance training with heavy loads, and the development of BCRL. Material and methods. This was a descriptive study. Population: Women treated for breast cancer (n � 149), who had participated in the ‘ Body and Cancer ’ exercise intervention between 1 January 2010 and 31 December 2011 participated in a structured telephone interview. The average follow-up time was 14 months (range 4 – 26). A clinical diagnosis of BCRL reported by the participant was the primary outcome. Results. A total of 27.5% reported that they had been diagnosed with BCRL by a clinician. This was true for 44.4% with axillary node dissection. No statistically signifi cant association between strength gains during the exercise intervention, and the development of BCRL was observed, nor was self-reported participation in progressive resistance training with heavy loads up to three months post-intervention. Conclusion. The prevalence of BCRL among former “ Body and Cancer ” participants at follow-up was 27.5%. There appears to be no association between performing heavy resistance training during adjuvant treatment (chemotherapy/radiotherapy), and the development of BCRL. However randomized controlled trials should be performed to confi rm this observation.
Breast cancer-related lymphedema (BCRL) as a result of acquired interruption or damage to the axil-lary lymphatic system is associated with signifi cant physical, functional, and psychosocial burden [1].The incidence and prevalence of BCRL have been diffi cult to quantify due to a lack of a standardized measurement method and a uniform defi nition of what constitutes BCRL, as well as the lack of an evidence-based defi nition of transient versus chronic lymphedema [1 – 3]. Moreover, prevalence rates have been found to vary based on the surgery performed and the extent of adjuvant treatment ranging from 13% to 65% [4]. In a meta-analysis from 2013, Disipio et al. found a pooled estimate for incidence
of 16.6% based on 72 studies [1]. However, inci-dence rates varied depending on study design rang-ing from 8.4% in retrospective cohort studies to 21.4% in prospective cohort studies, as well as a result of diagnostic method ranging from 5.0% with lymphoscintigraphy to 28.2% when multiple mea-surement methods were applied. The incidence of BCRL seemed to increase with time up to two years from diagnosis or surgery (12 – � 24 months, 18.9%), after which a decrease in incidence was observed. Lastly, the incidence of BCRL was four times higher among women who had AND (19.9%) than in women who had sentinel node biopsy (SNB) (5.6%).
Acta Oncologica, 2014; 53: 216–225
ISSN 0284-186X print/ISSN 1651-226X online © 2014 Informa HealthcareDOI: 10.3109/0284186X.2013.844356
Dow
nloa
ded
by [
Cop
enha
gen
Uni
vers
ity L
ibra
ry]
at 0
4:33
09
Mar
ch 2
016
Heavy resistance training and lymphedema 217
There has been a longstanding concern that pro-gressive resistance training (PRT) increased the risk of developing BCRL [5]. However, a growing body of evidence indicates that PRT does not increase BCRL risk [5,6]. Furthermore, it is well demon-strated in the literature that PRT has a benefi cial effect on a number of the side- or late effects related to breast cancer treatment by positively impacting self-perceptions of body image [7], increasing vital-ity [8], lean body mass [9,10], bone mineral density [11], and muscular strength [9,10,12]. Indeed, 2010 guidelines from the American College of Sports Medicine (ACSM) [6] advocate PRT. How-ever, none of the seven studies that these guidelines are based on were conducted on patients undergo-ing adjuvant treatment (chemotherapy and/or radio-therapy). Furthermore, the heaviest loads lifted corresponded to three sets of 10 repetitions [12,13], considered moderate resistance [14]. Since the ACSM guidelines were published, four randomized controlled exercise trials utilizing PRT during adju-vant treatment have been performed [9,15 – 17]. Only one of these had BCRL as the primary out-come. Furthermore, maximum loads of 60 – 70% of 1 RM (moderate load) were the heaviest loads lifted. Recently, Cormie et al. conducted two studies which examined the safety of heavy resistance training in women with BCRL. The studies found that resis-tance training with heavy loads ( � 80% 1 RM) did not acutely exacerbate an existing lymphedema [18], and was found to be a safe training mode, associated with improvements in physical function and quality of life [19]. However, as these studies were performed in women with BCRL, a gap in knowledge exists concerning the safety of heavy load PRT in regard to BCRL risk. Therefore studies are needed that investigate the safety of PRT during adjuvant treatment with BCRL as the primary out-come, as well as PRT with heavier loads.
Originally a RCT (for details see Adamsen et al. [20]) ‘ Body and Cancer ’ (B & C) has been offered as an exercise intervention for cancer patients undergo-ing chemotherapy in the Copenhagen area since 2007. To date approximately 1300 participants rep-resenting over 21 diagnoses have participated in this six-week, nine-hour weekly, supervised multi-modal exercise intervention. Among the unique characteristics of this intervention is the utilization of low intensity components (relaxation- and body awareness training and massage) with high intensity components (aerobic- and resistance training).
Of interest for the present study are the high intensity days (Monday, Wednesday, Friday) where participants engage in a cardiovascular warm-up (esti-mated average intensity of 9 METs, 4.5 MET hours per training session), followed by PRT (estimated
average intensity of 5.5 METs, 4 MET hours per training session) and 15 – 30 minutes of interval train-ing on stationary bicycles with peak loads of 85 – 95% of each participants maximum heart rate (estimated average intensity of 15 METs, 3.75 MET hours per training session. Lastly, participants engage in relax-ation training lasting approximately 15 minutes.
Six machines are used during PRT: leg press, chest press, latissimus (lat.) pull down, abdominal crunch, lower back and knee extension (Technogym ® , Gambettola, Italy). Muscular strength is ascertained in all six resistance training machines at baseline and at the commencement of the intervention using the 1RM test [20]. Partici-pants are encouraged to lift loads corresponding to 2 – 3 sets of 8 – 12 repetitions at 70% 1RM the fi rst week, progressing to 80% 1RM the second week. From week three loads are lifted corresponding to three sets of 5 – 8 repetitions at 80 – 90% 1 RM. Par-ticipants who develop subjective (e.g. sensations of heaviness or swelling) or objective (e.g. visible swell-ing, pitting edema) signs of BCRL or experience exacerbations of an existing BCRL are instructed by the staff (physical therapists and trained nurse spe-cialists) to decrease loads or refrain from the lat. pull down and chest press exercises and are referred to hospital- or private practice lymphedema thera-pists for evaluation and treatment. No systematic registration of BCRL has ever been carried out.
Therefore, using a cross-sectional design, the purpose of the present study was to investigate the prevalence of BCRL in breast cancer patients who participated in B & C from 1 January 2010 to 31 December 2011. It was hypothesized that par-ticipation in this exercise intervention utilizing heavy load PRT ( � 80% 1 RM) was not associated with an increased risk of BCRL.
Material and methods
Recruitment
Breast cancer patients who had participated in the exercise intervention from 1 January 2010 to 31 December 2011 were identifi ed in the B & C database (n � 180). Participants came from four university hospitals in the Copenhagen area and were eligible for the exercise intervention if they had a diagnosis of breast cancer, had received at least one cycle of chemotherapy for advanced disease or as adjuvant treatment, had a WHO performance status of 0 or 1 and otherwise had been approved to participate by the treating oncologist. Medical records were searched for a clinician diagnosis of BCRL, recurrent cancer, and mortality status. Figure 1 details the recruitment and exclusion process, leaving a study sample of 149 women.
Dow
nloa
ded
by [
Cop
enha
gen
Uni
vers
ity L
ibra
ry]
at 0
4:33
09
Mar
ch 2
016
218 K. Bloomquist et al.
Data sources
Electronic medical records . Data regarding surgery and treatment as well as BCRL, recurrent cancer and mortality status were obtained from electronic medical records.
Structured telephone interview. A structured telephone interview was administered by one of the authors (KB) a research physical therapist affi liated with the exercise intervention, and lasted on average 15 minutes. Responses were recorded on a pre-printed form. All telephone interviews were obtained within a six-week period.
The primary outcome, a clinical diagnosis of BCRL, was ascertained by asking the participant if she had been diagnosed with lymphedema. She was defi ned as having BCRL if she answered “ yes ” . If the participant reported having been diagnosed with BCRL she also was asked to report when and by whom the diagnosis was made as well as which region was affected (hand, arm, breast, torso). Demographic, treatment, and training/physical activity characteristics were also obtained. More specifi cally, demographic characteristics included age, current BMI, relationship status, age of children living at home, education and current occupation. Treatment characteristics included whether surgery had been performed on the dominant/non-dominant side and whether they had been introduced to post-operative exercises for breast cancer patients. Furthermore, the interview supplemented any information lacking from the medical records. Behavioral characteristics included whether the par-ticipant had performed post-operative exercises before participating in the intervention, whether they had engaged in PRT 1 – 3 � /week between sur-gery and B & C, and whether they had engaged in
PRT 1 – 3 � /week post-intervention, and if so for how long, and with which loads. In addition, leisure time physical activity was explored using a validated method [21].
Arm circumference measurements. For participants answering “ yes ” to having been diagnosed with BCRL, circumference measurements (measured at the time of lymphedema assessment) were obtained from medical records. If no circumference measure-ments were noted in the medical records, measure-ments were obtained by contacting the clinician (e.g. rheumatologist, general practitioner, lym-phedema therapist, etc.) that had diagnosed the participant. No standardized protocol for measur-ing was used as each clinician had their own proto-col ranging from fi ve to seven measuring points. A participant was considered to have BCRL if an interlimb difference of � 2 cm at to two or more measures was reported [16].
B & C database. Baseline BMI and pre-illness physical activity levels [21] were obtained from the database, as well as baseline and post-intervention muscular strength (1 RM) of the upper (chest press) and lower body (leg press) and adherence to the intervention.
Statistical analysis
Statistical procedures were performed using the Statistical Package for Social Sciences (SPSS) software (version 19) for Windows. Descriptive sta-tistics are presented as proportions for categorical variables and as means and standard error (SE) for continuous variables unless otherwise noted. Mean changes in muscular strength (1 RM) after six weeks of training were assessed using a paired t-test, and were analyzed on a per-protocol (PP) basis, includ-ing only participants with baseline and six-week mea-surements as well as on an intention to treat (ITT) basis using baseline observation carried forward (BOCF). Point prevalence was calculated at the time of the present study [on average 14 months post-intervention (range 4 – 26)], and estimated ret-rospectively at the commencement of B & C and at 1, 2, 3, and 4 months post-B & C participation.
To compare differences between participants that had been diagnosed with BCRL and those that had not χ 2 -test and Fisher ’ s exact test were used to compare categorical variables. Where relevant categorical variables were dichotomized. Continuous variables were compared using two-sample t-tests. Levene ’ s test for equality of variances was performed and results presented use pooled variances unless otherwise noted. A two-tailed p � 0.05 was taken as evidence of statistical signifi cance. From the
Figure 1. Flow chart depicting selection of the study population derived from women treated for breast cancer who had participated in ‘ Body and Cancer ’ from January 2010 through December 2011.
Dow
nloa
ded
by [
Cop
enha
gen
Uni
vers
ity L
ibra
ry]
at 0
4:33
09
Mar
ch 2
016
Heavy resistance training and lymphedema 219
literature it was known that comparison studies were carried out on AND populations alone, and therefore a sub-analysis of participants with AND was performed.
Ethical considerations
The study was performed in accordance with the Helsinki Declaration, and approved by the Danish Data Protective Agency .
Results
Participant characteristics
Of the 158 women contacted, 94.3% (n � 149) were included in the study. The mean age was 47.7 years and 14.9% had children � 7 years of age living at home. Most were in a relationship (71.8%), had higher than a secondary education (86.0%) and were currently employed (73.8%), with over half (63.6%) describing their employment as being “ not physically demanding ” . The mean self-reported BMI was 24.1, with 35.6% classifi ed as overweight ( � 25). 41.6% had undergone breast ablation sur-gery and 60.4% had received AND, with 53.7% having undergone surgery on the non-dominant side. All had undergone chemotherapy, with 94.6% having received adjuvant chemotherapy. The majority of the women had received radiotherapy (80.5%), and 79.9% had received/were receiving endocrine treatment, while 15.4% were receiving/had received trastuzumubab.
B & C participation
On average participants had initiated B & C 16.5 (range 5.6 – 27.6) weeks after surgery, and had undergone 3.8 (range 1 – 8) cycles of chemotherapy. Over half (60.4%) had an adherence rate of at least 70% (17 of 24 training days) to the exercise interven-tion. Both the per-protocol (Table 1) and ITT (not shown) analyses revealed increases in upper and lower body muscular strength after six weeks of
training. Mean time from B & C termination to tele-phone interview participation was 14 months, ranging between 4 and 26 months. In total 17.4% (n � 26) had been fi nished with the intervention up to six months, 31.5% (n � 47) between 7 and 12 months and 38.3% (n � 57) between 13 and 24 months. 12.8% (n � 19) had participated in B & C more than two years previously.
Self-reported leisure time physical activity levels
Over half of the participants (70.9%) reported that they had been physically active at least three hours per week, of which 7.8% had been physically active more than four hours per week pre-illness. At follow-up, on average 14 months post-intervention, a shift was seen towards more physical activity as 78.5% currently reported being physically active at least three hours per week, of which 31.5% cur-rently were physically active more than four hours per week (p � 0.001).
Point prevalence of BCRL
The total prevalence 4 – 26 months post-intervention (mean 14) was 27.5% (Table II). A sub-analysis of the AND population revealed a prevalence of 44.4%. Six percent reported that they had been diagnosed with BCRL during the intervention increasing to 17.4% at four months post-interven-tion. In the AND population 10.0%, and 27.8%, respectively reported a BCRL diagnosis (Table II). All BCRL cases had received AND, with the excep-tion of one participant. Notably, among women with a diagnosis of BCRL one reported swelling in the hand only, three in the breast only, and one in the torso only.
Arm circumference measurements
Arm circumference measurements were taken at the time of lymphedema assessment by various clinicians at eight different facilities (two hospitals, six private
Table I. Strength outcomes after six weeks in ‘ Body and Cancer ’ .
Total Population AND Population
Total Population No BCRL BCRL No BCRL BCRL
Variable nBaseline
Mean (SE)6 weeks
Mean (SE) Δ Mean
Mean (SE) n Δ Mean
(SE) n Δ Mean
(SE) p-value † n Δ Mean
(SE) n Δ Mean
(SE) p-value †
1RM Chest Press (kg) 125 27.2 (0.66) 31.9 (0.70) 4.7 (0.43) ∗ 93 4.6 (0.47) 32 5.0 (0.98) 0.68 41 4.3 (0.69) 31 4.5 (0.88) 0.82
1RM Leg Press (kg) 132 76.0 (2.00) 94.8 (2.45) 18.8 (1.75) ∗ 96 16.5 (1.82) 36 24.7 (4.07) 0.07 45 14.9 (2.48) 35 23.7 (4.06) 0.06
Δ Change between baseline and 6 weeks. ∗ (p-value � 0.05). † No BCRL as reference.
Dow
nloa
ded
by [
Cop
enha
gen
Uni
vers
ity L
ibra
ry]
at 0
4:33
09
Mar
ch 2
016
220 K. Bloomquist et al.
practice lymphedema therapists) with varying proto-cols. Measurements were obtained for 38 of the 41 (92.7%) participants diagnosed with BCRL. Of these, 47.4% had an interlimb difference of � 2 cm at two or more measures. Thus according to this diag-nostic method, and with the criteria applied, preva-lence at the study point was 12.3%, increasing from 3.4% during the intervention, to 10.3% four months post-intervention. In the AND population, point prevalence at the study period was 19.5%, ranging between 5.8% and 16.1%, respectively (Table II).
Variable differences
A larger percentage of participants diagnosed with BCRL had a BMI � 25 (p � 0.023), had undergone AND (p � 0.000) and had received radiotherapy (p � 0.005) (Table III). In contrast fewer had received trastuzumubab (p � 0.040). Over 90% of the par-ticipants diagnosed with BCRL had performed post-surgery exercises focusing on range of motion, at least 3 � /week before initiating the B & C interven-tion, compared to 68% in the no BCRL group. No between group differences were noted in regard to PRT before or after B & C (Table III), nor to strength development after six weeks of training (Table I).
Variable differences in the AND population
Sub-analysis of the AND population revealed that more participants diagnosed with BCRL currently were overweight (p � 0.001), or had been overweight at baseline (p � 0.017) (Table IV). No between group differences were found in regard to post-surgery exercises. However, 83.5% of the AND population had performed these exercises in comparison to 60.3% that had received SNB (p � 0.003), thus the between group difference (No BCRL/BCRL) found in the total population was associated with axillary surgery. Similarly, no between group difference was found in regard to radiotherapy. However, 93.3% in the AND population had received radiotherapy in com-parison to 62.3% in the SNB population (p � 0.000).
In contrast to the total population, no between group difference was found in regard to trastuzu-mubab treatment, however no association to axillary surgery was found. No between group differences were noted in regard to PRT before or after the inter-vention (Table IV), nor to strength development after six weeks of training (Table I).
Discussion
The prevalence of BCRL, 4 – 26 months after participation in B & C, was 27.5%. Sub-analysis revealed a prevalence rate of 44.4% amongst par-ticipants who had undergone AND. More partici-pants in the group diagnosed with BCRL were overweight and had undergone radiotherapy and AND. No associations were found between per-forming heavy resistance training and the develop-ment of BCRL.
Comparison to intervention studies during adjuvant treatment
Total population. The estimated prevalence of women reporting that they had been diagnosed with BCRL during the exercise intervention was 6.0%. These results are similar to Kilbreath et al. [16] that reported a BCRL incidence of 7 – 11% (depending on the measurement method applied) after an eight-week training intervention ultilizing moderate loads. The estimated prevalence had increased to 17.4% four months post-B & C in comparison to 7 – 8% six months post-intervention in Kilbreath ’ s study. However, using the same measurement method and criteria (arm circumference differences � 2 cm at two or more measures) the rate of BCRL was 10.3% in the present study and 7% in the Kilbreath study.
AND population. Among participants with AND, the post-intervention prevalence was 10.0%, increasing to 27.8% four months post-B & C. Comparably, in the Kilbreath study, between 20% and 33% had
Table II. Point prevalence of self-reported diagnosed lymphedema and arm circumference measurements in relation to participation in the intervention. Values are numbers of participants (percentages).
Time in relation to participation in ‘Body and Cancer’
Diagnosed BCRLTotal population
(n � 149)
Circumference � 2Total population
(n � 146) †
Diagnosed BCRLAND population
(n � 90)
Circumference � 2AND population
(n � 87) †
During intervention 9 (6.0) 5 (3.4) 9 (10.0) 5 (5.8)Within 1 month post-intervention 16 (10.7) 10 (6.8) 16 (17.8) 10 (11.5)1 – 2 months post-intervention 21 (14.1) 11 (7.5) 21 (23.3) 10 (11.5)2 – 3 months post-intervention 23 (15.4) 13 (8.9) 23 (25.6) 12 (13.7)3 – 4 months post-intervention 26 (17.4) 15 (10.3) 25 (27.8) 14 (16.1)Total at study ∗ 41 (27.5) 18 (12.3) 40 (44.4) 17 (19.5)
∗ On average 14 months (4 – 26 months) post-intervention. † Circumference measurements not available for 3 participants.
Dow
nloa
ded
by [
Cop
enha
gen
Uni
vers
ity L
ibra
ry]
at 0
4:33
09
Mar
ch 2
016
Heavy resistance training and lymphedema 221
Table III. Characteristics of participants with and without BCRL (n � 149). Values are numbers (percentages) unless stated otherwise.
Demographic characteristicsNo BCRL (n � 108)
BCRL (n � 41) p-value
Age mean (SD) 47.8 (8.7) 47.7 (7.9) 0.939Children in care � 7 years 18 (16.7) 4 (9.8) 0.438Married, cohabitating or in a relationship 79 (73.1) 28 (68.3) 0.548Education � secondary school 90 (83.3) 38 (92.7) 0.190Employed (full/part time) 80 (74.1) 30 (73.2) 1.00Not physically demanding work 50 (46.3) 20 (48.8) 0.936Moderately physically demanding work 25 (23.1) 9 (22.0)Very physically demanding work 5 (4.6) 1 (2.4) Health and medical characteristics Baseline BMI � 25 ∗ 43 (40.2) 20 (50.0) 0.350 Current BMI � 25 33 (31.0) 21 (51.2) 0.023 Breast ablation 44 (40.7) 18 (43.9) 0.871 Axillary node dissection 50 (46.3) 40 (97.6) 0.000 Non-dominant arm 56 (51.9) 24 (58.5) 0.581Chemotherapy3 � CE � 3 � docetaxel 73 (67.6) 29 (70.7) 0.6206 � CT 28 (25.9) 11 (26.8)Other 7 (6.5) 1 (2.4) Received radiotherapy 81 (75.0) 39 (95.1) 0.005 Received endocrine treatment 85 (78.7) 34 (82.9) 0.652 Received trastuzumubab 21 (19.4) 2 (4.9) 0.040 Physical activity level (self-reported) Pre-illness † Sedentary 4 (3.9) 1 (2.8) 0.585 Walking or cycling for pleasure 27 (26.0) 9 (25.0) Regular physical exercise, at least 3 h/week 66 (63.5) 23 (63.9) Intense physical activity � 4 h/week 7 (6.7) 5 (4.6)Present time Sedentary 2 (1.9) 1 (2.4) 0.473 Walking or cycling for pleasure 19 (17.6) 10 (24.4) Regular physical exercise at least 3 h/week 55 (50.9) 15 (36.6) Intense physical activity � 4 h/week 32 (29.6) 15 (36.6) Training Performed exercises prescribed post-surgery ‡ No 32 (31.7) 3 (7.5) 0.010 3 � weekly 16 (15.8) 7 (17.5) Daily 53 (52.5) 30 (75.0)PRT between surgery and ‘ Body and Cancer ’ ‡ 18 (17.8) 10 (25.0) 0.355PRT 3 months after ‘ Body and Cancer ’ 56 (51.9) 23 (56.0) 0.715Utilized 2 – 3 sets of 5 – 8 RM 29 (26.9) 15 (37.5) 0.325Adherence � 70% while in ‘ Body and Cancer ’ 70 (64.8) 20 (48.8) 0.092
∗ (n � 141, (n � 40 BCRL, n � 107 no BCRL)) due to missing data; † [n � 141, (n � 36 BCRL, n � 104 no BCRL)] due to missing data; ‡ [n � 141, (n � 40 BCRL, n � 101 no BCRL)] participants receiving neo-adjuvant; (n � 5) or chemotherapy for advanced disease (n � 3) not included.
developed BCRL post-intervention and 15 – 30% six months post-intervention. Courneya et al. reported an incidence rate of 3.7%, using water displacement, after a median of 17 weeks of PRT during adjuvant chemotherapy [9]. Notably, none of these women had received radiotherapy, and no follow-up mea-sures were reported. In a study by Sagen et al. participants initiated the intervention within the fi rst week of surgery [17]. After three months of strength training with light to moderate loads, 5% had developed BCRL (water displacement). At two years post-surgery the incidence rate was 13%. This stands in contrast to the present study with 44.4%
reporting that they had been diagnosed with BCRL 8 – 28 months post-surgery. However due to inherent differences in study design (RCT/cross-sectional), differing measurement methods and treatment bur-den, caution should be applied when interpreting these diverging results.
RCT versus cross-sectional studies. Inherent differences in study design make it diffi cult to compare results from the controlled framework of a RCT with results from a cross-sectional study. Participants were excluded from the RCTs if they had undergone reconstructive surgery [9], had metastatic cancer
Dow
nloa
ded
by [
Cop
enha
gen
Uni
vers
ity L
ibra
ry]
at 0
4:33
09
Mar
ch 2
016
222 K. Bloomquist et al.
Table IV. Sub-analysis in the AND population (n � 90). Characteristics of participants with and without BCRL. Values are numbers (percentages) unless stated otherwise.
Demographic characteristicsNo BCRL (n � 50)
BCRL (n � 40) p - value
Age mean (SD) 49.2 (9.0) 47.8 (8.0) 0.436Children in care � 7 years 9 (18.0) 4 (10.0) 0.371Married, cohabitating or in a relationship 37 (74.0) 28 (70.0) 0.813Education � secondary school 44 (88.0) 37 (92.5) 0.726Employed (full/part time) 40 (80.0) 29 (72.5) 0.458
Not physically demanding work 27 (54.0) 19 (47.5) 0.832Moderately physically demanding work 11 (22.0) 9 (22.5)Very physically demanding work 2 (4.0) 1 (2.5)
Health and medical characteristics Baseline BMI � 25 ∗ 13 (26.0) 20 (51.3) 0.017 Study BMI � 25 9 (18.0) 21 (52.5) 0.001 Breast ablation 25 (50.0) 18 (45.0) 0.676Non-dominant arm 32 (64.0) 23 (57.5) 0.664Chemotherapy3 � CE � 3 � docetaxel 33 (66.0) 29 (72.5) 0.5086 � CT 13 (26.0) 10 (25.0)Other 4 (8.0) 1 (2.5)Received radiotherapy 46 (92.0) 38 (95.0) 0.689Received endocrine treatment 45 (90.0) 33 (82.5) 0.358Received trastuzumubab 8 (16.0) 2 (5.0) 0.175 Physical activity level (self-reported) Pre-illness † Sedentary 1 (2.1) 1 (2.8) 0.717 Walking or cycling for pleasure 11 (22.9) 9 (25.0) Regular physical exercise, at least 3 h/week 34 (70.8) 23 (63.9) Intense physical activity � 4 h/week 2 (4.2) 3 (8.3)Present Sedentary 0 (0.0) 1 (2.5) 0.326 Walking or cycling for pleasure 7 (14.0) 10 (25.0) Regular physical exercise at least 3 h/week 25 (50.0) 15 (37.5) Intense physical activity � 4 h/week 18 (36.0) 14 (35.0) Training Performed exercises prescribed post-surgery ‡ No 10 (21.7) 3 (7.7) 0.1923 � weekly 8 (17.4) 7 (17.9)Daily 28 (60.9) 29 (74.4)PRT 1-3x/wk between surgery and ’ Body and Cancer ’ ‡ 13 (28.3) 10 (25.6) 1.000PRT 1-3x/wk 3 months after ’ Body and Cancer ’ 24 (48.0) 22 (55.0) 0.532Utilized 2 – 3 sets of 5 – 8 RM 14 (28.0) 14 (35.0) 0.769Adherence � 70% while in ‘ Body and Cancer ’ 35 (70.0) 19 (47.5) 0.051
∗ [n � 84, (n � 39 BCRL; n � 50 no BCRL)] due to missing data; † (n � 84) due to missing data; ‡ [n � 85,(n � 39 BCRL; n � 46 no BCRL)] participants receiving neo-adjuvant (n � 4) or chemotherapy for advanced disease (n � 1) not included.
[16,17], or bilateral breast cancer [16], or if they had a pre-existing upper limb impairment [16,17]. Furthermore, participants were screened and excluded if they presented with BCRL. In the pres-ent study, none of these exclusion criteria were applied and no pre-intervention BCRL screening took place, thus participants could have initiated B & C with an undiagnosed BCRL. Moreover, BCRL was in focus in the RCTs, and participants received treatment upon any signs or symptoms of BCRL during both the intervention and follow-up periods. This likely decreased the incidence of BCRL in comparison to the present study where participants
were encouraged to seek treatment by the B & C staff upon symptoms of BCRL, but “ were on their own ” after the intervention period.
Measurement methods. It is well established that the diagnostic method used in a given observational or intervention study infl uences the incidence or prev-alence found [3]. This is illustrated in a recent study that found baseline prevalence rates ranging from 22% (arm circumference) to 52% (self-reported swelling) depending on the four measurement meth-ods applied [3]. Similarly, Ahmed et al. reported
Dow
nloa
ded
by [
Cop
enha
gen
Uni
vers
ity L
ibra
ry]
at 0
4:33
09
Mar
ch 2
016
Heavy resistance training and lymphedema 223
baseline BCRL prevalence rates of 17.4% (arm cir-cumference), 43.4% (self-reported swelling), and 30.4% (self-reported clinician diagnosis) [22]. In the present study, under half (47.4%) of the women that had reported a clinician diagnosis of BCRL pre-sented with an interlimb difference � 2 cm at two or more measures, indicating that if this measurement method had been used as the primary measure, prevalence rates had been considerably lower.
Treatment burden. Breast cancer treatment is tailored to the individual breast cancer status, thus women treated for breast cancer is a heterogeneous group [4]. This is exemplifi ed in a Danish population-based study that found that 1 – 3 years post-surgery, BCRL prevalence rates ranged from 13% to 65% based on treatment burden alone [4]. The study illustrates well the complexity regarding overall prevalences in this group, and should be taken into consideration in the interpretation of prevalence and incidence rates.
Known risk factors
In accordance with risk factors identifi ed by Disipio et al. as being supported by a high level of evidence [1], more women in the group diagnosed with BCRL had a current BMI � 25, and had received AND. Moreover, sub-analysis of the AND population revealed that more women had a BMI � 25 at baseline and were currently overweight in the group diagnosed with BCRL. In the total population, more women that had received radiotherapy reported a diagnosis of BCRL. This is also in accordance with Disipio et al. that found a moderate level of evidence support-ing radiotherapy as a risk factor [1]. However, this association was not observed in the AND popula-tion, perhaps due to a small sample size. Nonetheless, these fi ndings are in accordance with results found by Sagen et al. [17], who found that being overweight was the only predictor of developing BCRL among study participants who all had received AND.
An unexpected fi nding, the results showed that more women had received trastuzumubab in the no BCRL group. This difference was not observed in the AND population, however no association to axillary surgery was found. No studies were identi-fi ed by the author that have observed a protective effect of this adjuvant treatment, and as this study is merely a descriptive study with a small population no conclusions can or should be drawn. Rather it should be used as an observation and perhaps a cat-alyst for further study.
Physical activity levels
Questions regarding leisure time physical activity lev-els were validated [21] and had been administered
to participants at the initiation of the B & C training intervention, and could therefore be used to describe any trends in time.
In total 63.1% reported pre-illness physical activ-ity levels corresponding to at least three hours per week, and 7.8% over four hours per week. Physical activity levels at follow-up (4 – 26 months post-intervention) had shifted to an increase in physical activity with 47.0% reporting that they presently were exercising at least three hours per week, and 31.5% exercising over four.
However, these results are likely infl ated due to pleasing bias as approximately half of the partici-pants had previously met the author due to her affi liation with B & C as a trainer. Nonetheless, this is an interesting fi nding as previous studies have found that women who undergo treatment for breast cancer tend to decrease physical activity levels [23]. More importantly this shift was also seen in par-ticipants diagnosed with BCRL, indicating that maintaining and possibly increasing a physically active lifestyle is possible with BCRL. Furthermore, this fi nding indicates that participation in an inten-sive, multimodal, six-week intervention promoting physical activity during adjuvant treatment perhaps can play a role in lasting lifestyle changes.
Post-surgery exercises
Self-reported adherence to post-surgery exercise was high, with 75.2% of the total population and 83.5% of the AND population performing these exercises at least three times per week before initiating B & C. Despite this, 90.2% of the participants that devel-oped BCRL reported that they regularly had performed these exercises, thus no protective effect was indicated. However, post-operative exercises focusing on mobility of the shoulder joint and stretching of muscles related to breast cancer surgery play an important role in restoring normal function of the affected limb [24] and should therefore be an integrated part of a rehabilitation program.
PRT during and after B & C
Strength outcome measures and adherence related to B & C. No between group differences in post-intervention 1 RM strength or adherence were found. These results indicate that there was no difference in strength training intensity between the women that did and did not develop BCRL.
PRT after B & C. Over 50% reported that they had continued to perform PRT 1 – 3 � /week for a mini-mum of three months, with no between group differences. These results are in line with previous
Dow
nloa
ded
by [
Cop
enha
gen
Uni
vers
ity L
ibra
ry]
at 0
4:33
09
Mar
ch 2
016
224 K. Bloomquist et al.
intervention studies, fi nding no associations between PRT and an increased risk of BCRL. Approximately 30% reported that they had lifted loads of 5 – 8 repetitions (heavy), with no between group differ-ences. This fi nding indicates that heavy PRT after B & C was not associated with a self-reported clinician diagnosis of BCRL, however further inves-tigation using a robust design is warranted.
Strengths and limitations
The participants. A total of 83% of the identifi ed B & C participants made up the study population. Twelve women with pre-existing BCRL were excluded as one of the main objectives of the study was to describe association between participation in B & C and the development of BCRL. Thus, when considering the prevalence of BCRL in the study population, these participants should be taken into account.
Moreover, due to ethical considerations, nine women were not contacted as it had been noted in the medical records that a recurrent cancer had recently been detected or was under investigation, and three were deceased. A further two declined to participate for personal reasons, and fi ve were uncontactable. Thus, the BCRL status of these women is not known.
Design. As this study utilized a cross-sectional design, and with a small study sample, it does not offer the possibility of drawing conclusions regarding causal-ity, but can merely describe factors associated with identifi ed cases of BCRL as defi ned in this study. Thus, though results do not indicate an association between heavy resistance training and the develop-ment of BCRL, conclusions regarding the “ safety ” of heavy resistance training cannot be drawn. None-theless, the observations from this study are in line with studies from Cormie et al. [18,19], who found that heavy load PRT was a safe training modality for persons with an existing arm lymphedema, lending credibility to the results of the present study.
Structured telephone interview. The response rate to the telephone interview was high (94.3%). Furthermore, there was a 100% completion rate amongst respond-ers indicating that this was an evident method for obtaining data. The structured telephone interview was designed for the present study and was not vali-dated. Furthermore, some of the questions were ret-rospective in nature, thus a risk of recall bias exists.
BCRL defi nition considerations. Ideally, objective measurements would have been performed on all participants, however, this was beyond the scope of the study and was not possible. Thus, reporting
a clinical diagnosis of BCRL was utilized as the primary defi nition, despite numerous uncertain-ties. Firstly, this provides just one estimate of prev-alence and therefore does not give the possibility to determine whether it was transient lymphedema dissipating over time, or chronic BCRL. A longi-tudinal study (n � 211) evaluating BCRL on fi ve occasions up to 18 months post-surgery, found that almost 60% of the women that had showed evidence of BCRL, had transitory symptoms whereby the lymphedema dissipated [2]. This is important to bear in mind when comparing the follow-up incidence estimates in the Kilbreath and Sagen studies where all participants were evalu-ated anew, whereby transient lymphedema cases were identifi ed and therefore not included as an incident BCRL case. In the present study all BCRL cases were accumulated and thus, the fi nal esti-mated prevalence is likely overestimated. Second, BCRL was determined by at least eight different clinicians, with no standardized protocols, cut-offs or criteria for when a participant presented with BCRL, lending uncertainty as to the real preva-lence in the study population. However, in com-parison to studies with well-defi ned cut-offs and controlled frameworks, the present study is prag-matic and refl ects the reality of clinical practice. Finally, in the present study BCRL was not limited to the arm, and should be considered when inter-preting the results of the study.
Despite the limitations, the present study with its high response rate and 100% completion rate amongst responders, offers conceivable prevalence estimates of BCRL amongst former participants of this exercise intervention. Furthermore, the data obtained are consistent, with no contradictory fi nd-ings, lending credibility to the results.
Studies investigating BCRL are confronted with a number of challenges. Variations in treatment burden alone, infl uence prevalence rates. Moreover utilization of different measurement methods and criteria applied to defi ne chronic BCRL, thwart comparisons between studies and limits the knowl-edge gained, thus international consensus needs to be found. Nonetheless, irrespective of the diagnostic criteria applied, studies have found PRT to be safe following breast cancer, with this study adding to the growing database. There is considerable rational for promoting PRT during adjuvant treatment as PRT performed alone or in combination with other exer-cise modalities has been shown to relieve a number of chemotherapy-induced side effects [9,16,20]. Furthermore, though strength gains are seen with lighter loads, heavy PRT is an effective training method and necessary for achieving strength gains in trained individuals [25].
Dow
nloa
ded
by [
Cop
enha
gen
Uni
vers
ity L
ibra
ry]
at 0
4:33
09
Mar
ch 2
016
Heavy resistance training and lymphedema 225
Conclusion
The prevalence of self-reported clinician diagnosed BCRL, 4 – 26 months after participation in a reha-bilitation exercise intervention utilizing heavy resis-tance training, was 27.5%. Sub-analysis revealed a prevalence rate of 44.4% amongst participants who had undergone axillary node dissection.
There appears to be no association between performing heavy resistance training during adjuvant therapy, and the development of BCRL. However randomized controlled trials should be performed to confi rm this observation.
Acknowledgments
Thanks to all the participants who donated their time and shared their experiences.
Declaration of interest: The authors report no confl icts of interest. The authors alone are respon-sible for the content and writing of the paper.
References
DiSipio T , Rye S , Newman B , Hayes S . Incidence of unilateral [1] arm lymphoedema after breast cancer: A systematic review and meta-analysis . Lancet Oncol 2013 ; 14 : 500 – 15 . Hayes SC , Janda M , Cornish B , Battistutta D , Newman B . [2] Lymphedema after breast cancer: Incidence, risk factors, and effect on upper body function . J Clin Oncol 2008 ; 26 : 3536 – 42 . Hayes SC , Speck RM , Reimet E , Stark A , Schmitz KH . [3] Does the effect of weight lifting on lymphedema following breast cancer differ by diagnostic method: Results from a randomized controlled trial . Breast Cancer Res Treat 2011 ; 130 : 227 – 34 . Gartner R , Jensen MB , Kronborg L , Ewertz M , Kehlet H , [4] Kroman N . Self-reported arm-lymphedema and functional impairment after breast cancer treatment – a nationwide study of prevalence and associated factors . Breast 2010 ; 19 : 506 – 15 . Kwan ML , Cohn JC , Armer JM , Stewart BR , Cormier JN . [5] Exercise in patients with lymphedema: A systematic review of the contemporary literature . J Cancer Surviv 2011 ; 5 : 320 – 36 . Schmitz KH , Courneya KS , Matthews C , Demark-[6] Wahnefried W , Galvao DA , Pinto BM , et al . American College of Sports Medicine roundtable on exercise guidelines for cancer survivors . Med Sci Sport Exer 2010 ; 42 : 1409 – 26 . Speck RM , Gross CR , Hormes JM , Ahmed RL , Lytle LA , [7] Hwang WT , et al . Changes in the Body Image and Relationship Scale following a one-year strength training trial for breast cancer survivors with or at risk for lymphedema . Breast Cancer Res Treat 2010 ; 121 : 421 – 30 . McKenzie DC , Kalda AL . Effect of upper extremity exercise [8] on secondary lymphedema in breast cancer patients: A pilot study . J Clin Oncol 2003 ; 21 : 463 – 6 . Courneya KS , Segal RJ , Mackey JR , Gelmon K , Reid RD , [9] Friedenreich CM , et al . Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: A multicenter randomized controlled trial . J Clin Oncol 2007 ; 25 : 4396 – 404 .
Battaglini C , Bottaro M , Dennehy C , Rae L , Shields E , [10] Kirk D , et al . The effects of an individualized exercise intervention on body composition in breast cancer patients undergoing treatment . Sao Paulo Med J 2007 ; 125 : 22 – 8 . Winters-Stone KM , Dobek J , Nail L , Bennett JA , Leo [11] MC , Naik A , et al . Strength training stops bone loss and builds muscle in postmenopausal breast cancer survivors: A randomized, controlled trial . Breast Cancer Res Treat 2011 ; 127 : 447 – 56 . Schmitz KH , Ahmed RL , Troxel A , Cheville A , Smith R , [12] Lewis-Grant L , et al . Weight lifting in women with breast-cancer-related lymphedema . New Engl J Med 2009 ; 361 : 664 – 73 . Hayes SC , Reul-Hirche H , Turner J . Exercise and secondary [13] lymphedema: Safety, potential benefi ts, and research issues . Med Sci Sport Exer 2009 ; 41 : 483 – 9 . Baechle TR , Earle RW , Wathen D . Essentials of strength [14] training and conditioning . In: Baechle TR , Earle RW , editors. Human Kinetics , 2nd ed . Champaign IL: National Strength and Conditioning Association ; 2000 . Anderson RT , Kimmick GG , McCoy TP , Hopkins J , [15] Levine E , Miller G , et al . A randomized trial of exercise on well-being and function following breast cancer surgery: The RESTORE trial . J Cancer Surviv 2012 ; 6 : 172 – 81 . Kilbreath SL , Refshauge KM , Beith JM , Ward LC , Lee M , [16] Simpson JM , et al . Upper limb progressive resistance training and stretching exercises following surgery for early breast cancer: A randomized controlled trial . Breast Cancer Res Treat 2012 ; 133 : 667 – 76 . Sagen A , Karesen R , Risberg MA . Physical activity for [17] the affected limb and arm lymphedema after breast cancer surgery. A prospective, randomized controlled trial with two years follow-up . Acta Oncol 2009 ; 48 : 1102 – 10 . Cormie P , Galvao DA , Spry N , Newton RU . Neither heavy [18] nor light load resistance exercise acutely exacerbates lymphedema in breast cancer survivor . Integr Cancer Ther 2013 ; 12 : 423 – 32 . Cormie P , Pumpa K , Galvao DA , Turner E , Spry N , [19] Saunders C , et al . Is it safe and effi cacious for women with lymphedema secondary to breast cancer to lift heavy weights during exercise: A randomised controlled trial . J Cancer Surviv 2013 ; 7 : 413 – 24 . Adamsen L , Quist M , Andersen C , Moller T , Herrstedt J , [20] Kronborg D , et al . Effect of a multimodal high intensity exercise intervention in cancer patients undergoing chemo-therapy: Randomised controlled trial . Br Med J 2009 ; 339 : b3410 . Saltin B , Grimby G . Physiological analysis of middle-aged [21] and old former athletes . Comparison with still active athletes of the same ages. Circulation 1968 ; 38 : 1104 – 15 . Ahmed RL , Thomas W , Yee D , Schmitz KH . Randomized [22] controlled trial of weight training and lymphedema in breast cancer survivors . J Clin Oncol 2006 ; 24 : 2765 – 72 . Irwin ML , Smith AW , McTiernan A , Ballard-Barbash R , [23] Cronin K , Gilliland FD , et al . Infl uence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: The health, eating, activity, and lifestyle study . J Clin Oncol 2008 ; 26 : 3958 – 64 . McNeely ML , Campbell K , Ospina M , Rowe BH , Dabbs K , [24] Klassen TP , et al . Exercise interventions for upper-limb dysfunction due to breast cancer treatment . Cochrane Database Syst Rev 2010 : CD005211 . American College of Sports Medicine position stand . [25] Progression models in resistance training for healthy adults . Med Sci Sport Exer 2009 ; 41 : 687 – 708 .
Dow
nloa
ded
by [
Cop
enha
gen
Uni
vers
ity L
ibra
ry]
at 0
4:33
09
Mar
ch 2
016
Paper II
STUDY PROTOCOL Open Access
A randomized cross-over trial to detectdifferences in arm volume after low- andheavy-load resistance exercise amongpatients receiving adjuvant chemotherapyfor breast cancer at risk for armlymphedema: study protocolKira Bloomquist1* , Sandi Hayes2, Lis Adamsen1, Tom Møller1, Karl Bach Christensen3, Bent Ejlertsen4
and Peter Oturai5
Abstract
Background: In an effort to reduce the risk of breast cancer-related arm lymphedema, patients are commonlyadvised to avoid heavy lifting, impacting activities of daily living and resistance exercise prescription. This advicelacks evidence, with no prospective studies investigating arm volume changes after resistance exercise with heavyloads in this population. The purpose of this study is to determine acute changes in arm volume after a session oflow- and heavy-load resistance exercise among women undergoing adjuvant chemotherapy for breast cancer atrisk for arm lymphedema.
Methods/Design: This is a randomized cross-over trial. Participants: Women receiving adjuvant chemotherapy forbreast cancer who have undergone axillary lymph node dissection will be recruited from rehabilitation centers inthe Copenhagen area. Intervention: Participants will be randomly assigned to engage in a low- (two sets of 15–20repetition maximum) and heavy-load (three sets of 5–8 repetition maximum) upper-extremity resistance exercisesession with a one week wash-out period between sessions. Outcome: Changes in extracellular fluid (L-Dex score)and arm volume (ml) will be assessed using bioimpedance spectroscopy and dual-energy x-ray absorptiometry,respectively. Symptom severity related to arm lymphedema will be determined using a visual analogue scale (heaviness,swelling, pain, tightness). Measurements will be taken immediately pre- and post-exercise, and 24- and 72-hourspost-exercise. Sample size: A sample size of 20 participants was calculated based on changes in L-Dex scores betweenbaseline and 72-hours post exercise sessions.
Discussion: Findings from this study are relevant for exercise prescription guidelines, as well as recommendationsregarding participating in activities of daily living for women following surgery for breast cancer and who may be atrisk of developing arm lymphedema.
Trial registration: Current Controlled Trials ISRCTN97332727. Registered 12 February 2015.
Keywords: Lymphedema, Breast cancer, Resistance exercise
* Correspondence: [email protected] Hospitals Centre for Health Research (UCSF), CopenhagenUniversity Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø,DenmarkFull list of author information is available at the end of the article
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Bloomquist et al. BMC Cancer (2016) 16:517 DOI 10.1186/s12885-016-2548-y
BackgroundApproximately 20 % of breast cancer survivors developbreast cancer-related arm lymphedema BCRL [1], withan estimated 80 % of cases presenting within the firsttwo years of diagnosis [2]. It is associated with signifi-cant impairments in gross and fine motor skills affect-ing work, home and personal care functions, as well asrecreational and social relationships [3, 4]. While theetiology of BCRL is unknown [1, 5], findings from asystematic review and meta-analysis from 2013 [1] in-cluding 72 studies demonstrate that axillary lymphnode dissection, more extensive breast surgery, radio-therapy, chemotherapy, being overweight or obese andphysical inactivity are consistently associated with in-creased BCRL risk [1].Participation in resistance exercise has been found
to be a safe and effective exercise modality amongbreast cancer survivors at risk of BCRL [6, 7], and isassociated with increases in lean muscle mass andstrength, which in turn positively effect physical func-tion and ability. Furthermore, findings from a recentmeta-analysis [6] suggest that resistance exercise canreduce the risk of BCRL versus control conditions(OR = 0.53 (95 % CI 0.31–0.91); I2 = 0 %). However, thecurrent evidence-base is derived from studies that haveevaluated resistance exercise intensities considered to below to moderately heavy (60–80 % of 1 repetition max-imum (RM) or 8–15 RM) [6, 7]. Yet, exercise scienceliterature indicates that heavy-load resistance exercise(80–90 % 1RM or 5–8 RM) [8] is more effective than low-to moderate-load resistance exercise in generating musclestrength gains [9]. There is therefore a clear need for stud-ies evaluating the safety of heavy-load resistance exercisein the at-risk population [7].In a novel study by Cormie et al. [10], which evalu-
ated the effect of low- and heavy-load resistance exer-cise among a sample with BCRL, lymphedema statusand lymphedema symptoms remained stable immedi-ately after exercise, and 24- and 72-hours after exercise,irrespective of load. While these findings provide im-portant information for women with BCRL, the pur-pose of this study is to determine acute changes inextracellular fluid, arm volume and associated lymph-edema symptoms after a session of low- and heavy-loadresistance exercise in women at risk for BCRL. It is hy-pothesized that no interlimb differences in extracellularfluid, arm volume or lymphedema-associated symptomseverity will be observed over time or between resist-ance exercise loads.
DesignThis study is a randomized, cross-over trial (Table 1here).
Table 1 Trial registration data
Trial registration data
Primary registry and trialidentify number
Current Controlled Trials ISRCTN97332727.
Date of registration inprimary registry
12 February 2015.
Secondary identifyingnumbers
H-3-2014-147, 30-1430
Source of monetary ormaterial support
University Hospitals Centre for HealthResearch, Copenhagen University HospitalRigshospitalet
Primary sponsor University Hospitals Centre for Health Research,Copenhagen University Hospital Rigshospitalet
Secondary sponsor
Contact for publicqueries
KB, MHS, PhD-stud. [email protected], (45)35347362, Blegdamsvej 9 (afsnit 9701), 2100Copenhagen
Contract for scientificqueries
KB, MHS, PhD-stud. [email protected], (45)35347362, Blegdamsvej 9 (afsnit 9701), 2100Copenhagen
Public title A trial to detect differences in arm volumeafter low- and heavy-load resistance exerciseamong patients receiving adjuvantchemotherapy for breast cancer at riskfor arm lymphedema: Study Protocol
Scientific title A randomized cross-over trial to detectdifferences in arm volume after low- andheavy-load resistance exercise among patientsreceiving adjuvant chemotherapy for breastcancer at risk for arm lymphedema:Study Protocol
Countries ofrecruitment
Denmark
Health condition orproblem studied
Breast cancer-related arm lymphedema
Intervention Heavy vs low load resistance exercise for theupper extremities
Key inclusion andexclusion criteria
Inclusion criteria: > 18 years of age, unilateralbreast surgery, axillary node dissection,undergoing adjuvant chemotherapy for breastcancer
Exclusion criteria: Previously treated for breastcancer, diagnosis of BCRL and/or currentlyreceiving treatment for BCRL, or havingconditions hampering resistance exercise ofthe upper body, or having participated inregular upper-body heavy resistance exerciseduring the last month
Study type Interventional
Randomized cross-over, assessor blinded
Safety
Date of first enrolment 31-03-2015
Target sample size 40
Recruitment status Recruiting
Primary outcome Arm extracellular fluid (L-dex score) post-,24- and 72 h post exercise
Key secondaryoutcomes
Arm volume (ml) post-, 24- and 72 h postexercise
Bloomquist et al. BMC Cancer (2016) 16:517 Page 2 of 8
MethodsParticipants / RecruitmentTwenty women allocated to adjuvant chemotherapy forbreast cancer consisting of three cycles of 3-weekly epiru-bicin followed by three cyles of 3-weekly docetaxel will berecruited from municipality lead rehabilitation centers inthe Copenhagen area and from a waiting list to the Bodyand Cancer program [11, 12], at the University HospitalsCenter for Health Research (UCSF) at the CopenhagenUniversity Hospital, Rigshospitalet. All patients will bescreened for inclusion by health professionals (nurse orphysical therapist) at the respective centers. Potential par-ticipants fulfilling inclusion criteria; over 18 years of age,unilateral breast surgery, axillary node dissection, and ini-tiating /undergoing adjuvant chemotherapy for breastcancer (stage I - III) will be contacted during their firstthree cycles of chemotherapy (Fig. 1). Patients previouslytreated for breast cancer, with a diagnosis of BCRL and/orcurrently receiving treatment for lymphedema, or havingconditions hampering resistance exercise of the upperbody, or having participated in regular (>1 × / week)upper-body heavy resistance exercise during the lastmonth will be excluded.Those fulfilling study criteria and expressing interest
in study participation will thereafter be screened forBCRL by the first author after the third cycle of chemo-therapy, using bioimpedance spectroscopy (BIS). Fur-thermore, in accordance with common toxicity criteria(CTC) v3.0 lymphedema criteria for the limb [13], pa-tients will be visually inspected to detect differences insigns of swelling between arms. Those presenting withBCRL, defined as a lymphedema index (L-Dex) score of10 or greater [14–16] (as assessed by BIS), and/or visualsigns of swelling (obscuration of anatomic architectureor pitting edema) of the at-risk arm [13] will be referredfor treatment, and will not be included in the study.Written and oral information regarding the study will
be delivered by the first author, as well as obtainment ofinformed written consent.
Concealed randomizationPrior to the study, a computer-generated random se-quence will be generated by an external researcher nototherwise affiliated with the study, and concealed inopaque envelopes. Group assignment will be disclosedto the first author by telephone after study inclusion andparticipation in the familiarization period. Participantswill be allocated using a 1:1 ratio to partake in eitherlow- or heavy-load resistance exercise first.
Exercise sessionsParticipants will engage in a familiarization period, com-prising of two training sessions up to one week apart, afterthe third cycle of chemotherapy. Each session will startwith a 10- minute aerobic warm-up using a cross-trainer(Glidex, Technogym®, Gamettola, Italy). During the firstfamiliarization session participants will be introduced tofour upper-body exercises (chest press, latissimus pulldown, triceps extension (Technogym®, Gamettola, Italy)and biceps curl (free weights)) followed by a 1RM strengthtest in each exercise. At the second familiarization session,two sets of 10–15 RM will be performed and a new 1RMstrength test will be undertaken to ensure accuracy of sub-sequent exercise prescription. Participants will engage inthe first experimental session after the first cycle of doce-taxel (fourth chemotherapy), followed by a wash-outperiod of 6 days. Two sets of 15–20 RM of each exercisewill be performed during low-load resistance exercise andthree sets of 5–8 RM during heavy-load. All sets will beperformed to muscle fatigue in sessions individually super-vised by the first author (a physical therapist with experi-ence in exercise prescription for women with breastcancer) at training facilities located at Rigshospitalet.
Outcomes (pre- and post, 24- and 72-hours after resist-ance exercise)Measurements will be performed by medical technicianswith no knowledge of group (low- / high-load first) allo-cation at the Department of Clinical Physiology and
Fig. 1 Study time line
Bloomquist et al. BMC Cancer (2016) 16:517 Page 3 of 8
Nuclear Medicine at the Copenhagen University Hos-pital, Rigshospitalet. Participants are advised to maintaintheir normal activities during study participation. At allassessment points, participants will be asked about theirphysical activities, and any extraordinary activities willbe recorded.
Primary outcomeExtracellular fluid BIS (SFB7, Impedimed, Brisbane,Australia) directly measures the impedance of extracel-lular fluid and has a high reliability for detecting BCRL[14, 16, 17] (intraclass correlation coefficient (ICC) =0,99) [18]. Participants will be positioned in supine witharms and legs slightly abducted from the trunk withpalms facing down. Utilizing the principle of equipoten-tials, four single tab electrodes will be placed in a tetrapo-lar arrangement [17]. Measurement electrodes will beplaced on the dorsum of the wrist midway between thestyloid processes, with current drive electrodes placed fivecentimeters distally on the dorsal side over the third meta-carpal of the hand, and approximately midway on thethird metatarsal on the dorsum of the foot [17, 19]. Eachlimb will be measured at a range of frequencies using themanufacturer’s software. The ratio of impedance betweenthe at-risk and non-affected limb will be calculated andconverted into a L-Dex score.
Secondary outcomesArm volume Dual energy x-ray absorptiometry (DXA)(Lunar Prodigy Advanced Scanner, GE Healthcare,Madison, WI) measures tissue composition using a three-compartment model that is sensitive to changes in upper-limb tissue composition [20, 21]. Using previously deriveddensities for: fat (0.9 g/ml); lean mass (1.1 g/ml); bonemineral content (BMC) (1.85 g/ml), the measured DXAtissue weights will be transformed into estimated arm vol-umes [20, 21].Participants will be positioned on the scan-table, lying
supine with the arm separated from the trunk. If neces-sary a Velcro band will be used over the breast to ensurespace between the arm and truncus. Each arm will bescanned separately. Small animal software (Encore ver-sion 14.10) will be used to analyze the scans as describedby Gjorup et al. [20]. Scans will be point typed wheresoft tissue is marked as bone, whereafter regions ofinterest (ROIs) will be drawn around the hand and thearm on every scan (Fig. 2). All scans will be analyzed byone examiner (last author) with experience in analyzingDXA scans.Subjective assessment of symptoms The severity of symp-
toms related to arm lymphedema including swelling,heaviness, pain and tightness, will be monitored using avisual analogue scale, whereby 0 represents no discomfortand 10 is indicative of very severe discomfort [10].
Fig. 2 DXA regions of interest
Bloomquist et al. BMC Cancer (2016) 16:517 Page 4 of 8
One year follow-upStatistically, it is assumed that some of the participantsin the study will develop arm lymphedema. Furthermore,previous studies have found a highly variable response toresistance exercise [10, 22]. A one year exploratory, hy-pothesis generating follow-up has been planned as itprovides an opportunity to determine how many partici-pants develop arm lymphedema and whether individualvariability in response to the resistance exercise ses-sions is related to subsequent lymphedema incidence.Measurements will include 1RM strength in the fourresistance exercises, DXA, BIS and symptom severity(VAS) as described, and a structured interview by thefirst author to determine other known and theoreticalrisk factors.
BlindingAll data collection and analysis will be conducted bystudy personnel with no knowledge of group (low- /high-load first) allocation.
Sample size and analytical planThe sample size calculation is based on changes in L-Dexscores between baseline and 72 h post-resistance exercisesessions. From results of Cormie et al. [10] we hypothesizethe standard deviation in the distribution to be 1.9 units.No published normative change scores exist for the at-riskpopulation, as well as no evidence regarding a thresholdfor a clinically significant acute change. For patients withBCRL a change score of 2L-Dex units is considered clinic-ally relevant based on clinical experience. We believe thatan L-Dex of 2 units is too conservative in the at-risk popu-lation, and have therefore set a threshold at 3L-Dex units.Thus, if there is no difference between groups, then 18 pa-tients are required to be 90 % sure that the limits of atwo-sided 90 % confidence interval will exclude a differ-ence in means of more than 3.0. To allow for possibledrop-outs we plan to include 20 patients.Data will be analyzed using the Statistical Package for
Social Sciences (SPSS) software (version 19) for Windows(IBM SPSS, Chicago, IL). Analysis will include standarddescriptive statistics and both intention to treat and per-protocol analysis will be performed. Using a generalizedestimating equations framework for continuous outcomesto determine time (baseline, pre-, post, 24- and 72 h) andintervention (low-/ heavy-load) effects, the interactionbetween time and intervention will be considered [23].Two-tailed p < 0.05 will be taken as evidence of statis-tical significance.
Safety and ethical considerationsThe treating oncologist will have the overall responsibil-ity for the participants. All personal data will be treatedin accordance with existing rules and regulations.
A full body DXA scan utilizes weak x-rays and is notconsidered dangerous [24]. In this study, since only armswill be scanned the radiation dose is estimated to be0.0001 mSv for both arms. Eight scans result in a totaldose of 0.0008 mSv, which is less than the backgroundradiation an average person is exposed to in one day inDenmark.As about 20 % of women treated for breast cancer de-
velop BCRL [1], it is expected that some of the partici-pants in this study will develop BCRL. Participation inthis study involves regular assessment of the at-risk armduring the study period, using some of the best technol-ogy to date. This allows for early detection of BCRL,which in turn would render a better prognosis, as earlydetection is associated with a better outcome [4]. If par-ticipants develop signs of swelling or an L-Dex scorepersisting over one week during the familiarization orexperimental study period, they will be referred to thetreating oncologist for lymphedema treatment and willbe withdrawn from the study.A completed SPIRIT checklist is included as Additional
file 1.
DiscussionParticipating in resistance exercise during adjuvant chemo-therapy for breast cancer has been associated with increasesin muscle strength [25–29], lean body mass [25, 28], andself-esteem [25], and has been found to mitigate fatigueand to maintain quality of life [29]. Furthermore, there isevidence to suggest that resistance exercise might be asso-ciated with a higher completion rate of planned chemo-therapy [25]. Moreover, generalized edema characterizedby an increase in the size of the interstitial compartmentof extracellular fluid is a potential side effect to taxane-based chemotherapy [30, 31]. Thus, swelling as a conse-quence of increased fluid in addition to an impairment oflymph fluid transport, could potentially contribute toswelling of the at-risk arm. Hypothetically, this could bethwarted by resistance exercise due to increased lymphclearance likely through the effects of the muscle pump[32, 33], lending additional rationale for instigating resist-ance exercise during adjuvant chemotherapy.To our knowledge, studies investigating the safety and
efficacy of resistance exercise in patients at risk for BCRLhave utilized low- to moderate-resistance exercise inten-sities [6, 7], with only one cross-sectional study [11] inves-tigating heavy-load resistance exercise. Indeed, in a paperidentifying the top 10 research questions related to phys-ical activity and cancer survivorship, Courneya et al. [34]highlighted the need for studies investigating safety andoptimal exercise prescription, and specifically the role ofvigorous-intensity activity, as important research areas [34].The rational for utilizing heavy-load resistance exercise
is supported by exercise science literature that indicates
Bloomquist et al. BMC Cancer (2016) 16:517 Page 5 of 8
that this higher training intensity can lead to additionalbenefits as a dose–response relationship exists betweenthe load of resistance exercise and gains in muscularstructure and function [35, 36]. Furthermore, breast can-cer survivors may suffer from losses of bone mass (par-ticularly those on aromatase inhibitors), at least in partas a result of the catabolic effects of treatment. Resist-ance exercise interventions with lower loads have notyielded significant training effects on bone mineral dens-ity [27, 37]. It has been postulated that the absence of ameasurable effect on bone mass density is related to theadaptive nature of bone that requires heavier loads [37],as heavy-load resistance exercise has been identified asan osteogenic exercise modality in women without can-cer [38]. Thus, establishing the safety of heavy-load re-sistance exercise is prudent and of significance for thebreast cancer population.No standardized measurement method exists to diag-
nose or monitor BCRL [1, 20, 21], with a variety of tech-niques and definitions used. Early BCRL is characterizedby an increase in extracellular fluid. Indirect measure-ment methods such as circumference, water displace-ment, and perometry measure volume of the entire limbto detect small changes in extracellular fluid which ac-counts for approximately 25 % of the total limb, and donot differentiate between tissue types [5, 18]. In contrast,BIS directly measures lymph fluid change by measuringthe impedance to a low level electrical current allowingfor a sensitive [21, 39] and reliable measurement methodto detect extracellular fluid changes among at-risk breastcancer survivors [39]. Furthermore, BIS is fast and easyto administer, and as impedance measures are reportedas an L-Dex value, inherent volume differences associatedwith hand dominance are taken into account [5, 39]. How-ever, BIS loses its sensitivity to monitor BCRL over timeas lymphedema progresses into later stages, whereby theexcess extracellular fluid initially characterizing BCRL isreplaced with adipose tissue [5, 21].DXA is another measurement method that can differen-
tiate between tissue types giving an estimate of BMC, fatmass and lean mass where the lean mass component in-cludes extracellular fluid [20, 21, 40]. DXA has been foundto be sensitive to changes in tissue composition, making itan ideal measurement method to monitor BCRL over timeas fluid components are replaced with adipose tissue. Fur-thermore, DXA allows for analysis of separate regions ofthe arm, of potential clinical importance for patientswhere swelling is confined to a specific region of the armor hand [20, 21, 40, 41]. In this study we scan the armsseparately and use software with a high resolution allow-ing for more precise definition of ROIs and the possibilityto define bone and soft tissue manually as described byGjorup et al., with a low inter-rater variation (ICC ≥,9990)[20]. To the authors’ knowledge, this is the first time that
DXA, with this software, will be used to detect volumechanges in the BCRL at-risk population adding new in-sights into the application of this measurement method.This exploratory study utilizes a cross-over design to de-
termine acute changes in extracellular fluid and arm vol-ume. This design lends more statistical power, with thepractical advantage of a smaller sample size, as between-patient variation is inherently eliminated [42], providing aframework for an efficient comparison between the tworesistance exercise loads. However, this study can onlyprovide us with information regarding extracellular fluidand arm volume changes after one resistance exercise ses-sion, limiting the generalizability to repeated resistance ex-ercise training and long-term effects on arm volume.Nonetheless, this study can lend initial evidence regardingthe safety of heavy-load lifting and can help guide futurestudies and optimal exercise prescription.Finally, women at risk for BCRL still receive risk reduc-
tion advice including avoiding heavy lifting [43, 44]. Thisadvice can lead to women being apprehensive about liftingheavy loads with consequences for daily living (e.g., notlifting children, groceries, etc.). However, this advice is notbased on research and knowledge gained from this studycan provide a preliminary evidence base for guiding riskreduction practices involving intermittent heavy-load ac-tivity necessary for daily living.
Additional file
Additional file 1: SPIRIT checklist. (DOC 121 kb)
AbbreviationsAND, axillary lymph node dissection; BCRL, breast cancer-related armlymphedema; BIS, bioimpedance spectroscopy; CTC, common toxicitycriteria; DXA, dual-energy x-ray absorptiometry; ICC, intraclass correlationcoefficient; L-Dex, lymphedema index; ROI, region of interest
AcknowledgmentsWe would like to thank exercise physiologist Christian Lillelund for hiscontribution to the conception of the study.
FundingThis study is internally funded by the University Hospitals Centre for HealthResearch (UCSF), Copenhagen University Hospital, Rigshospitalet. UCSF is alsothe trial sponsor and play a role in the conception, execution, analysis andinterpretation of data.
Availability of data and materialA data management plan has been approved by the regional Danish DataProtection Agency (30-1430). No data monitoring committee has beenformed for the study.The datasets supporting the conclusions of the study are stored in a securedatabase at the Copenhagen University Hospital, Rigshospitalet and willbecome available as additional files upon publication of a results article.
Authors’ contributionsKB: Conception and design, drafting of manuscript and final approval forpublication. SH: Conception and design, drafting of manuscript and finalapproval for publication. LA: Conception and design, drafting of manuscriptand final approval for publication. TM: Conception and design, drafting ofmanuscript and final approval for publication. KBC: Design and final approval
Bloomquist et al. BMC Cancer (2016) 16:517 Page 6 of 8
for publication. BE: Design and final approval for publication. PO: Conceptionand design, drafting of manuscript and final approval for publication.
Authors’ informationKB: PhD-student, MHS, PTSH: Professor, Principal research fellow, PhDLA: Professor, PhD, RN, SociologistTM: Associate Professor, PhD, MPH, RNKBC: Associate Professor, StatisticianBE: Professor, Chief PhysicianPO: Chief Physician
Competing interestsThe authors declare that they have no competing interests.
Consent for publicationNot applicable
Ethics approval and consent to participateThis study has been approved by the Danish Capital Regional EthicsCommittee (H-3-2014-147). All participants will provide written informedconsent.If protocol modifications are necessary, amendments to the trial registrieswill be made after approval from the ethics committee.
DisseminationResults from the trial will be disseminated through publication andpresentation at relevant conferences and seminars regardless of themagnitude or direction of effect.
Author details1University Hospitals Centre for Health Research (UCSF), CopenhagenUniversity Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø,Denmark. 2Institute of Health and Biomedical Innovation, QueenslandUniversity of Technology, 60 Musk Avenue, Kelvin Grove Urban Village, KelvinGrove, Queensland 4059, Australia. 3Department of Public Health; Section ofBiostatistics, University of Copenhagen, Øster Farimagsgade 5, 1014Copenhagen K, Denmark. 4DBCG, Afsnit 2501, Copenhagen UniversityHospital, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark. 5Department ofClinical Physiology, Nuclear Medicine and PET, Copenhagen UniversityHospital, Blegdamsvej 9, 2100 Copenhagen, Denmark.
Received: 28 December 2015 Accepted: 11 July 2016
References1. DiSipio T, Rye S, Newman B, Hayes S. Incidence of unilateral arm
lymphoedema after breast cancer: a systematic review and meta-analysis.Lancet Oncol. 2013;14(6):500–15.
2. Norman SA, Localio AR, Potashnik SL, Simoes Torpey HA, Kallan MJ, WeberAL, Miller LT, Demichele A, Solin LJ. Lymphedema in breast cancer survivors:incidence, degree, time course, treatment, and symptoms. J Clin Oncol.2009;27(3):390–7.
3. Morgan PA, Franks PJ, Moffatt CJ. Health-related quality of life withlymphoedema: a review of the literature. Int Wound J. 2005;2(1):47–62.
4. Hayes SC, Johansson K, Stout NL, Prosnitz R, Armer JM, Gabram S, SchmitzKH. Upper-body morbidity after breast cancer: incidence and evidence forevaluation, prevention, and management within a prospective surveillancemodel of care. Cancer. 2012;118(8 Suppl):2237–49.
5. Hayes SC, Speck RM, Reimet E, Stark A, Schmitz KH. Does the effect ofweight lifting on lymphedema following breast cancer differ by diagnosticmethod: results from a randomized controlled trial. Breast Cancer Res Treat.2011;130(1):227–34.
6. Cheema BS, Kilbreath SL, Fahey PP, Delaney GP, Atlantis E. Safety andefficacy of progressive resistance training in breast cancer: a systematicreview and meta-analysis. Breast Cancer Res Treat. 2014;148(2):249–68.
7. Paramanandam VS, Roberts D. Weight training is not harmful for womenwith breast cancer-related lymphoedema: a systematic review. J Physiother.2014;60(3):136–43.
8. Baechle TR, ERW, Wathen D. Essentials of strength training andconditioning. In: Baechle TR, editor. Human kinetics. 2nd ed. Champaign:ERW; 2000.
9. American College of Sports Medicine position stand. Progression modelsin resistance training for healthy adults. Med Sci Sports Exerc. 2009;41(3):687–708.
10. Cormie P, Galvao DA, Spry N, Newton RU. Neither heavy nor light loadresistance exercise acutely exacerbates lymphedema in breast cancersurvivors. Integr Cancer Ther. 2013;12(5):423-32.
11. Bloomquist K, Karlsmark T, Christensen KB, Adamsen L. Heavy resistancetraining and lymphedema: prevalence of breast cancer-related lymphedemain participants of an exercise intervention utilizing heavy load resistancetraining. Acta Oncol. 2014;53(2):216–25.
12. Adamsen L, Quist M, Andersen C, Moller T, Herrstedt J, Kronborg D,Baadsgaard MT, Vistisen K, Midtgaard J, Christiansen B, et al. Effect of amultimodal high intensity exercise intervention in cancer patientsundergoing chemotherapy: randomised controlled trial. BMJ. 2009;339:b3410.
13. Cheville AL, McGarvey CL, Petrek JA, Russo SA, Thiadens SR, Taylor ME.The grading of lymphedema in oncology clinical trials. Semin Radiat Oncol.2003;13(3):214–25.
14. Ward LC, Dylke E, Czerniec S, Isenring E, Kilbreath SL. Confirmation of thereference impedance ratios used for assessment of breast cancer-relatedlymphedema by bioelectrical impedance spectroscopy. Lymphat Res Biol.2011;9(1):47–51.
15. Hayes SC, Rye S, Disipio T, Yates P, Bashford J, Pyke C, Saunders C, Battistutta D,Eakin E. Exercise for health: a randomized, controlled trial evaluating theimpact of a pragmatic, translational exercise intervention on the quality of life,function and treatment-related side effects following breast cancer. BreastCancer Res Treat. 2013;137(1):175–86.
16. Ward LC, Bunce IH, Cornish BH, Mirolo BR, Thomas BJ, Jones LC. Multi-frequency bioelectrical impedance augments the diagnosis andmanagement of lymphoedema in post-mastectomy patients. Eur J ClinInvest. 1992;22(11):751–4.
17. Cornish BH, Jacobs A, Thomas BJ, Ward LC. Optimizing electrode sites forsegmental bioimpedance measurements. Physiol Meas. 1999;20(3):241–50.
18. Cornish BH, Thomas BJ, Ward LC, Hirst C, Bunce IH. A new technique for thequantification of peripheral edema with application in both unilateral andbilateral cases. Angiology. 2002;53(1):41–7.
19. Kilbreath SL, Lee MJ, Refshauge KM, Beith JM, Ward LC, Simpson JM, Black D.Transient swelling versus lymphoedema in the first year following surgery forbreast cancer. Support Care Cancer. 2013;21(8):2207–15.
20. Gjorup C, Zerahn B, Hendel HW. Assessment of volume measurement ofbreast cancer-related lymphedema by three methods: circumferencemeasurement, water displacement, and dual energy X-ray absorptiometry.Lymphat Res Biol. 2010;8(2):111–9.
21. Newman AL, Rosenthall L, Towers A, Hodgson P, Shay CA, Tidhar D,Vigano A, Kilgour RD. Determining the precision of dual energy x-rayabsorptiometry and bioelectric impedance spectroscopy in the assessment ofbreast cancer-related lymphedema. Lymphat Res Biol. 2013;11(2):104–9.
22. Lane KN, Dolan LB, Worsley D, McKenzie DC. Upper extremity lymphaticfunction at rest and during exercise in breast cancer survivors with andwithout lymphedema compared with healthy controls. J Appl Physiol(1985). 2007;103(3):917–25.
23. Cormie P, Singh B, Hayes S, Peake JM, Galvao DA, Taaffe DR, Spry N, Nosaka K,Cornish B, Schmitz KH et al.: Acute inflammatory response to low-, moderate-,and high-load resistance exercise in women with breast cancer-relatedlymphedema. Int Cancer Ther. 2015;e-pub ahead of print.
24. Baim S, Wilson CR, Lewiecki EM, Luckey MM, Downs Jr RW, Lentle BC.Precision assessment and radiation safety for dual-energy X-rayabsorptiometry: position paper of the International Society for ClinicalDensitometry. J Clin Densitom. 2005;8(4):371–8.
25. Courneya KS, Segal RJ, Mackey JR, Gelmon K, Reid RD, Friedenreich CM,Ladha AB, Proulx C, Vallance JK, Lane K, et al. Effects of aerobic andresistance exercise in breast cancer patients receiving adjuvantchemotherapy: a multicenter randomized controlled trial. J Clin Oncol. 2007;25(28):4396–404.
26. Courneya KS, McKenzie DC, Mackey JR, Gelmon K, Friedenreich CM, Yasui Y,Reid RD, Cook D, Jespersen D, Proulx C, et al. Effects of exercise dose andtype during breast cancer chemotherapy: multicenter randomized trial.J Natl Cancer Inst. 2013;105(23):1821–32.
Bloomquist et al. BMC Cancer (2016) 16:517 Page 7 of 8
27. Schwartz AL, Winters-Stone K, Gallucci B. Exercise effects on bone mineraldensity in women with breast cancer receiving adjuvant chemotherapy.Oncol Nurs Forum. 2007;34(3):627–33.
28. Battaglini C, Bottaro M, Dennehy C, Rae L, Shields E, Kirk D, Hackney AC.The effects of an individualized exercise intervention on body compositionin breast cancer patients undergoing treatment. Sao Paulo Med J. 2007;125(1):22–8.
29. Schmidt ME, Wiskemann J, Armbrust P, Schneeweiss A, Ulrich CM, SteindorfK. Effects of resistance exercise on fatigue and quality of life in breastcancer patients undergoing adjuvant chemotherapy: a randomizedcontrolled trial. Int J Cancer. 2015;137(2):471–80.
30. Bronstad A, Berg A, Reed RK. Effects of the taxanes paclitaxel and docetaxelon edema formation and interstitial fluid pressure. Am J Physiol Heart CircPhysiol. 2004;287(2):H963–8.
31. Qin YY, Li H, Guo XJ, Ye XF, Wei X, Zhou YH, Zhang XJ, Wang C, Qian W, Lu J,et al. Adjuvant chemotherapy, with or without taxanes, in early or operablebreast cancer: a meta-analysis of 19 randomized trials with 30698 patients.PLoS One. 2011;6(11):e26946.
32. Lane K, Worsley D, McKenzie D. Exercise and the lymphatic system:implications for breast-cancer survivors. Sports Med. 2005;35(6):461–71.
33. Goddard AA, Pierce CS, McLeod KJ. Reversal of lower limb edema by calfmuscle pump stimulation. J Cardiopulm Rehabil Prev. 2008;28(3):174–9.
34. Courneya KS, Rogers LQ, Campbell KL, Vallance JK, Friedenreich CM. Top 10research questions related to physical activity and cancer survivorship. ResQ Exerc Sport. 2015;86(2):107–16.
35. Fry AC. The role of resistance exercise intensity on muscle fibre adaptations.Sports Med. 2004;34(10):663–79.
36. Cormie P, Pumpa K, Galvao DA, Turner E, Spry N, Saunders C, Zissiadis Y,Newton RU. Is it safe and efficacious for women with lymphedemasecondary to breast cancer to lift heavy weights during exercise: arandomised controlled trial. J Cancer Surviv. 2013;7(3):413–24.
37. Winters-Stone KM, Laudermilk M, Woo K, Brown JC, Schmitz KH. Influence ofweight training on skeletal health of breast cancer survivors with or at riskfor breast cancer-related lymphedema. J Cancer Surviv. 2014;8(2):260–8.
38. Kohrt WM, Bloomfield SA, Little KD, Nelson ME, Yingling VR. AmericanCollege of Sports Medicine Position Stand: physical activity and bonehealth. Med Sci Sports Exerc. 2004;36(11):1985–96.
39. Fu MR, Cleland CM, Guth AA, Kayal M, Haber J, Cartwright F, Kleinman R,Kang Y, Scagliola J, Axelrod D. L-dex ratio in detecting breast cancer-relatedlymphedema: reliability, sensitivity, and specificity. Lymphology. 2013;46(2):85–96.
40. Brorson H, Ohlin K, Olsson G, Karlsson MK. Breast cancer-related chronic armlymphedema is associated with excess adipose and muscle tissue. LymphatRes Biol. 2009;7(1):3–10.
41. Czerniec SA, Ward LC, Meerkin JD, Kilbreath SL. Assessment of segmentalarm soft tissue composition in breast cancer-related lymphedema: a pilotstudy using dual energy X-ray absorptiometry and bioimpedancespectroscopy. Lymphat Res Biol. 2015;13(1):33–9.
42. Altman DG. Practical statistics for medical research. London: Chapman &Hall/CRC; 1991.
43. Binkley JM, Harris SR, Levangie PK, Pearl M, Guglielmino J, Kraus V, RowdenD. Patient perspectives on breast cancer treatment side effects and theprospective surveillance model for physical rehabilitation for women withbreast cancer. Cancer. 2012;118(8 Suppl):2207–16.
44. Lee TS, Kilbreath SL, Sullivan G, Refshauge KM, Beith JM. Patient perceptionsof arm care and exercise advice after breast cancer surgery. Oncol NursForum. 2010;37(1):85–91.
• We accept pre-submission inquiries
• Our selector tool helps you to find the most relevant journal
• We provide round the clock customer support
• Convenient online submission
• Thorough peer review
• Inclusion in PubMed and all major indexing services
• Maximum visibility for your research
Submit your manuscript atwww.biomedcentral.com/submit
Submit your next manuscript to BioMed Central and we will help you at every step:
Bloomquist et al. BMC Cancer (2016) 16:517 Page 8 of 8
Paper III
Heavy-Load Lifting: Acute Response in BreastCancer Survivors at Risk for Lymphedema
KIRA BLOOMQUIST1, PETER OTURAI2, MEGAN L. STEELE3, LIS ADAMSEN1, TOM MKLLER1,KARL BANG CHRISTENSEN4, BENT EJLERTSEN5, and SANDRA C. HAYES3
1University Hospitals Centre for Health Research (UCSF), Copenhagen University Hospital, Copenhagen, DENMARK;2Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Copenhagen, DENMARK;3Institute of Health and Biomedical Innovation, School of Public Health and Social Work, Queensland University of Technology,Kelvin Grove, Queensland, AUSTRALIA; 4Department of Public Health, Section of Biostatistics, University of Copenhagen,Copenhagen, DENMARK; and 5DBCG, Afsnit 2501, Copenhagen University Hospital, Copenhagen, DENMARK
ABSTRACT
BLOOMQUIST K., P. OTURAI, M. L. STEELE, L. ADAMSEN, T. MKLLER, K. B. CHRISTENSEN, B. EJLERTSEN, and S. C.
HAYES. Heavy-Load Lifting: Acute Response in Breast Cancer Survivors at Risk for Lymphedema. Med. Sci. Sports Exerc., Vol. 50,
No. 2, pp. 187–195, 2018. Purpose: Despite a paucity of evidence, prevention guidelines typically advise avoidance of heavy lifting in
an effort to protect against breast cancer–related lymphedema. This study compared acute responses in arm swelling and related
symptoms after low- and heavy-load resistance exercise among women at risk for lymphedema while receiving adjuvant taxane-based
chemotherapy. Methods: This is a randomized, crossover equivalence trial. Women receiving adjuvant taxane-based chemotherapy for
breast cancer who had undergone axillary lymph node dissection (n = 21) participated in low-load (60%–65% 1-repetition maximum,
two sets of 15–20 repetitions) and heavy-load (85%–90% 1-repetition maximum, three sets of 5–8 repetitions) upper-extremity resistance
exercise separated by a 1-wk wash-out period. Swelling was determined by bioimpedance spectroscopy and dual-energy x-ray absorp-
tiometry, with breast cancer–related lymphedema symptoms (heaviness, swelling, pain, tightness) reported using a numeric rating scale
(0–10). Order of low- versus heavy-load was randomized. All outcomes were assessed before, immediately after, and 24 and 72 h after
exercise. Generalized estimating equations were used to evaluate changes over time between groups, with equivalence between resistance
exercise loads determined using the principle of confidence interval inclusion. Results: The acute response to resistance exercise was
equivalent for all outcomes at all time points irrespective of loads lifted, with the exception of extracellular fluid at 72 h after exercise
with less swelling after heavy loads (estimated mean difference, j1.00; 95% confidence interval, j3.17 to 1.17). Conclusions: Low-
and heavy-load resistance exercise elicited similar acute responses in arm swelling and breast cancer–related lymphedema symptoms in
women at risk for lymphedema receiving adjuvant taxane-based chemotherapy. These represent important preliminary findings, which
can be used to inform future prospective evaluation of the long-term effects of repeated exposure to heavy-load resistance exercise. Key
Words: ARM SWELLING, BREAST CANCER, DOSE–RESPONSE, STRENGTH TRAINING
Breast cancer–related arm lymphedema (BCRL) is achronic condition initially characterized by regionalswelling of the arm or hand due to increases in
protein-rich extracellular fluid, affecting approximately 20%
of breast cancer survivors as a consequence of treatment(1,2). The adverse effects of BCRL are well described in theliterature, negatively affecting daily functions (3,4) and so-cial, emotional, and psychological well-being (4,5).
More extensive surgery to the chest wall, radiotherapy,chemotherapy, and being overweight and/or physically in-active have been consistently associated with increasedBCRL risk (1). However, the extent of lymph node removalis considered the strongest risk factor, with BCRL incidencefour times higher after axillary lymph node dissectioncompared with sentinel-node biopsy (1). Despite the high-quality evidence in support of specific risk factors, theability to predict who will develop BCRL is limited.
Historically, breast cancer survivors were advised to re-frain from resistance exercise as a means of preventingBCRL (6,7). However, results from systematic reviews ofclinical trials consistently indicate that resistance exerciseelicits gains in muscle strength and physical componentsof quality of life without increased risk for BCRL (6–9).
Address for correspondence: Kira Bloomquist, M.H.S, P.T., University Hospi-tals Centre for Health Research (UCSF), Copenhagen University Hospital,Blegdamsvej 9, 2100 Copenhagen, Denmark; E-mail: [email protected] for publication July 2017.Accepted for publication September 2017.
0195-9131/18/5002-0187/0MEDICINE & SCIENCE IN SPORTS & EXERCISE�Copyright� 2017 The Author(s). Published by Wolters Kluwer Health, Inc.on behalf of the American College of Sports Medicine. This is an open-access article distributed under the terms of the Creative CommonsAttribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND),where it is permissible to download and share the work provided it is properlycited. The work cannot be changed in any way or used commercially withoutpermission from the journal.
DOI: 10.1249/MSS.0000000000001443
187
CLIN
ICALSC
IENCES
Nonetheless, more work needs to be undertaken to confirmsafety of resistance exercise, because those considered at highrisk for BCRL do not reflect the target sample of studies in-cluded in these reviews. Specifically, only one study explic-itly included participants undergoing chemotherapy (10), ofwhich 31% received adjuvant taxane-based chemotherapy.This is of importance because generalized edema with ensu-ing arm swelling is a known side effect to this cytostatic agent(11). In addition, just two studies (10,12) specifically in-cluded women at risk for BCRL who had undergone axillarylymph node dissection, considered the greatest risk factor.
Limitations also exist with respect to exercise prescrip-tion because resistance load has not exceeded 80% of 1-repetition maximum (RM) or 8–12 repetitions in previousstudies evaluating resistance exercise and BCRL risk, be-cause of concerns that heavier loads would trigger BCRLdevelopment (6–9,13). However, exercise science literatureindicates that a dose–response relationship exists betweenloads lifted and gains in muscular structure and functionwith heavier loads shown to be more effective in elicitingstrength gains compared with lighter loads (14,15).
To date, two prospective studies including women withclinically stable BCRL who had been diagnosed with breastcancer at least a year before study inclusion have evaluatedthe potential of heavier-load resistance exercise using 6–10 RM (16,17). These studies found that the extent of armswelling and associated BCRL symptoms remained stableboth immediately after and 24 and 72 h after one bout ofresistance exercise (16), and after 12 wk of regular resistanceexercise irrespective of whether low or heavy loads werelifted (17). As such, these studies provide meaningful infor-mation for women with BCRL who have completed activetreatment (chemotherapy and radiotherapy). These findingscannot, however, be generalized to the at-risk populationundergoing taxane-based chemotherapy.
Therefore, the purpose of this study was to undertake aphase II trial to assess the initial lymphatic response to low-load compared with heavy-load resistance exercise in breastcancer survivors at risk for BCRL development. This wasundertaken by comparing acute changes in extracellular fluid,arm volume, and associated BCRL symptoms after a sessionof low- and heavy-load resistance exercise in women whohad undergone axillary lymph node dissection and were re-ceiving taxane-based chemotherapy during the conduct ofthis trial.
METHODS
Trial Design
Details of study design and methods have been previouslydescribed (18). In summary, this was a randomized, cross-over, equivalence trial whereby women participated in anexperimental low- and heavy-load upper-extremity resis-tance exercise session, with a 7-d wash-out period betweensessions (Fig. 1). It was hypothesized that response would be
similar between resistance exercise loads for all outcomes.The study protocol was approved by the Danish Data Pro-tection Agency (30-1430) and the Danish Capital RegionalEthics Committee (H-3-2014-147), and written informedconsent was obtained from all participants.
Participants
A convenience sample of women receiving standard ad-juvant chemotherapy for stage I–III breast cancer werescreened for eligibility (918 yr of age, first diagnosis ofbreast cancer, unilateral breast surgery, axillary node dis-section) at the Copenhagen Centre for Cancer and Healthand from a wait list to the Body & Cancer program (18,19)at the University Hospitals Centre for Health Research be-tween March 2015 and December 2016. Women with aknown clinical diagnosis of lymphedema or who had con-ditions limiting resistance exercise of the upper extremities(e.g., fibromyalgia, frozen shoulder) or who had participatedin regular upper-extremity heavy resistance exercise (91 perweek) during the last month were excluded (Fig. 1).
Those meeting eligibility were assessed for BCRL statusby the first author (K.B.), after the third cycle of chemo-therapy. BCRL was assessed using bioimpedance spectros-copy (BIS; SFB7; Impedimed, Brisbane, Australia [16,20,21])and a visual inspection to detect differences in swelling be-tween arms (Common Toxicity Criteria v3.0 [2]). Those withevidence of lymphedema according to standardized protocolsfor BIS (L-Dex 910) or visual inspection were then referredto a lymphedema therapist for further assessment and wereexcluded from participating in the study.
Exercise Sessions
All participants completed two familiarization sessions,followed by two experimental sessions (low- and heavy-loadsessions) at exercise facilities located at the research center.
All resistance exercise sessions lasted approximately 30 minincluding a 10-min aerobic-based warm-up (rowing orcross-trainer) at low-moderate intensity. All sessions weresupervised by the first author (K.B.) to ensure consistency ofwarm-up intensity and order of resistance exercises performed.None of the participants wore compression sleeves. Duringthe first familiarization session, participants were introducedto four upper-extremity exercises consisting of the biceps curlperformed with free weights, followed by the chest press,latissimus pull down, and triceps extension using resistanceexercise machines (Technogym�, Gamettola, Italy). Hereaf-ter, a 1RM strength test was performed in each exercise.During the second session, one set of 10–15 repetitions wasperformed, followed by a new 1RM strength test. Subse-quent resistance exercise prescription during the experi-mental sessions was based on these values. After completionof the familiarization sessions, resistance exercise load orderfor the experimental sessions was randomly allocated (i.e.,low or heavy load first) using a computer-generated random
http://www.acsm-msse.org188 Official Journal of the American College of Sports Medicine
CLINICALSC
IENCES
sequence (1/1 ratio). Women then participated in the experi-mental sessions, which entailed the 10-min aerobic-basedwarm-up, followed by the four resistance-based exercises.Resistance exercise load corresponded to 60%–65% 1RM(two sets of 15–20 repetitions) for the low-load session and85%–90% 1RM (three sets of 5–8 repetitions) for the heavy-load session. Participants were instructed to work to musclefatigue (until they were unable to maintain appropriate tech-nique) within the prescribed range and with rest periods of60–90 s between sets.
The experimental sessions were consistently performedon the same day of the week and at the same time of day,with all outcomes assessed before, immediately after (within30 min), and 24 and 72 h after resistance exercise sessions.Blinded data collection was performed by medical technicians.Participants were instructed to maintain normal upper-body
activities during the experimental period and to refrain fromextraordinary activities involving the upper extremities.
Primary Outcome
Extracellular fluid. BIS was used to directly measureand compare the impedance of extracellular fluid in the up-per extremities to electrical currents at a range of frequenciesaccording to the manufacturer_s software (20,21). Using theprinciple of equipotentials, four single-tab electrodes wereplaced in a tetrapolar arrangement and participants weremeasured in supine, with arms and legs abducted from thetrunk with palms facing down. To ensure accuracy, standardprotocols from the manufacturer were followed (e.g., emptybladder, no excessive exercise or caffeine consumptionwithin 2 h). The ratio of impedance (at R0) between the at-risk
FIGURE 1—Participant flow through resistance exercise and data collection sessions. RE, resistance exercise; SNB, sentinel-node biopsy.
HEAVY-LOAD RESISTANCE EXERCISE AND LYMPHEDEMA Medicine & Science in Sports & Exercised 189
CLIN
ICALSC
IENCES
and nonaffected arm was calculated and converted into anL-Dex score taking arm dominance into account.
Secondary Outcomes
Interarm volume percent difference. Measurementsof arm volume were obtained using dual-energy x-ray ab-sorptiometry (DXA; Lunar Prodigy Advanced Scanner; GEHealthcare, Madison, WI). DXAmeasures tissue compositionusing a three-compartment model that is sensitive to changesin upper-extremity tissue composition (21,22). Using previouslyderived densities for fat (0.9 gImLj1), lean mass (1.1 gImLj1)and bone mineral content (1.85 gImLj1), DXA measure-ments were converted into estimated arm volumes. Lyingsupine on the scan table with the arm separated from thetrunk, each arm was scanned separately. If necessary, a Velcroband or the free arm was placed over the breast to ensure spacebetween the arm and trunk. Small animal software (ENCOREversion 14.10) was used to analyze the scans as described byGjorup et al. (21,22). All scans were analyzed by a clinical ex-pert (P.O.) in DXA scan analysis. Interarm volume percent dif-ferences (at-risk arm minus unaffected arm/unaffected arm �100) were then calculated for each participant.
Subjective assessment of BCRL symptoms. Theseverity of symptoms related to BCRL was monitored usinga numeric rating scale. Participants rated their perceptions ofswelling, heaviness, pain, and tightness independently foreach arm on a scale from 0 (no discomfort) to 10 (very se-vere discomfort) (16,23).
Sample Size Calculation
Sample size calculation was based on changes in L-Dexscores between baseline and 72 h after resistance exercisesessions. From the results of Cormie et al. (16), it was hy-pothesized that the SD in the distribution of L-Dex scoreswould be 1.9 units. On the basis of clinical experience, forpatients with BCRL, a change score of 2.0 L-Dex units wouldbe considered clinically relevant. However, in the at-riskpopulation, no published normative change scores exist, nordoes evidence regarding a threshold for a clinically significantacute change. A change in 2.0 L-Dex units was deemed toosmall in the at-risk population, on the basis of the assumptionthat larger fluctuations would be seen within the normal rangewithout clinical relevance. Therefore, a priori, we set theclinically relevant threshold for change as being 3.0 L-Dexunits. Thus, if there was no difference between intensities,then 18 participants were needed to be 90% sure that thelimits of a two one-sided 95% confidence interval (CI) wouldexclude a difference in means of more than 3.0 L-Dex units.To allow for dropouts, 21 women were recruited.
Statistical Analyses
Descriptive statistics included counts (and percentages) forcategorical values and mean T SD for normally distributedcontinuous variables, unless otherwise noted. Individual
responses to resistance exercise loads were first assesseddescriptively, including determination of the proportion thatexceeded the predetermined clinically relevant threshold.Next, generalized estimating equations (GEE) (24) wereused to evaluate the effects of time (pre-, post-, 24 and 72 hpost-) and load (low/heavy load), and a time–load interac-tion. An exchangeable correlation structure was used tomodel the within-subject correlation of repeated measure-ments over time and across intensities.
To assess equivalence, the principle of CI inclusion wasused to calculate one-sided upper and lower 95% confidencelimits for all outcomes (25) (reported as two-sided 90%confidence limits). If the interval between the upper andlower confidence limits was within the predeterminedequivalence margin, equivalence between resistance exer-cise intensities was declared. For the primary outcome, themargin of equivalence was set at T3.0 L-Dex units. On thebasis of the findings by Stout et al. (26) that volume in-creases of 93% from preoperative measures were indicativeof subclinical BCRL, an equivalence margin of T3.0% wasused for interarm volume percent differences. For all sub-jective measures, interarm differences were calculated andan equivalence margin was set at T1.0 points. This thresholdwas based on previous findings that suggest a 2-point or30% change to be clinically meaningful for pain (23). Per-protocol principles were applied because this is consideredthe most conservative approach for determining equivalence (27).Analyses were conducted in R version 3.3.1 (28) using geepack1.2.0.1 for GEE modeling (29).
RESULTS
Participants. From the 216 women assessed for eligi-bility, 21 were eligible and consented to participate. Ofthese, 3 dropped out before initiation of the experimentalexercise sessions because of time constraints and injury (Fig. 1),1 discontinued participation after the 24-h postexercise as-sessment in week 1 because of logistical considerations, and17 (81%) completed all data collections.
Characteristics of the study population are presented inTable 1. Average age of participants was 45 yr, and meanbody mass index (BMI) was 25.3 kgImj2, with 11 (53%)participants presenting with a BMI of Q25.0 kgImj2. On av-erage, women had 22 axillary lymph nodes removed duringaxillary node dissection and 62% of the participants had re-ceived a mastectomy. As per eligibility criteria, all partici-pants received adjuvant taxane-based chemotherapy duringthe experimental sessions; however, the first 10 participantsreceived docetaxel, whereas the last 11 received paclitaxel,because standard chemotherapy changed midway through thestudy period.
Individual responses to resistanceexercise sessions.For L-Dex and interarm volume outcomes, individual re-sponses to resistance exercise sessions varied with no apparentgroup trend observed (Fig. 2A, B). For BCRL symptoms, wefound that most participants were asymptomatic before
http://www.acsm-msse.org190 Official Journal of the American College of Sports Medicine
CLINICALSC
IENCES
exercise and remained asymptomatic throughout the subse-quent data collections irrespective of loads lifted (Fig. 2C–F).
Deviations from predetermined thresholds. Whendata were described according to clinically relevant changesfrom preexercise, 16 women (89%) had experienced fluc-tuations in extracellular fluid beyond the predeterminedthreshold at one time point or more, ranging from j8.7 to6.8 L-Dex units. Almost twice as many had fluctuationsafter the low-load session (n = 12 (71%)) compared with thehigh-load session (n = 8 (44%); Table 2). Increases abovethe clinical threshold were observed for seven women (41%)after the low-load session, two of which had increased pre–post measures that remained elevated above the clinicallymeaningful threshold at 24 and 72 h after exercise (Fig. 2A).None of these women had clinically meaningful increases inL-Dex after heavy-load resistance exercise. Four women(22%) had increases in L-Dex after the heavy-load session.Of these, two were observed immediately after the heavyload session (one of these also showed an increase ininterarm volume percent difference; increases had dissipatedin both cases by the 24-h post–follow-up), whereas the othertwo were observed at 72 h after exercise.
For interarm volume, four (24%) women experiencedclinically meaningful fluctuations ranging from j4.1% to4.6%. Three (18%) participants experienced increases afterheavy-load exercise, with two seen immediately after exer-cise and one at 24 h after exercise (Fig. 2B). One participant(6%) experienced decreases after the low-load session im-mediately after exercise (Table 2). None of these observa-tions coincided with other outcome measures (except for thepreviously described L-Dex pre–post measure).
For BCRL symptoms, we found that eight (44%) womenresponded with fluctuations ranging from j7 to 3 units.Specifically, six (33%) women reported decreases in symp-toms, with reductions observed after exercise and sustainedover the subsequent time points, and were equally distrib-uted between resistance exercise load conditions (Table 2).
Increases in symptoms were reported by two (11%) women.One woman reported increases in pain and tightness at 24-hpost–heavy-load exercise (Fig. 2D, E), whereas the other par-ticipant experienced increases in heaviness and swelling afterexercise after the heavy-load session (Fig. 2C, F), and an in-crease in pain 24 h after the low-load session (Fig. 2D). Noneof these increases were sustained at the 72-h postsessionfollow-up.
An overview of unadjusted means and SD for all out-comes at each time point is presented in Table 3.
L-Dex. The estimated mean difference between re-sistance exercise loads and associated two-sided 90% CI forL-Dex scores were contained within the predeterminedequivalence margin of T3.0 units immediately and 24 h afterresistance exercise indicating equivalence between intensi-ties (j0.97 (j2.09 to 0.16) and j0.14 (j1.63 to 1.35),respectively; Table 4). However, at 72 h after exercise, thelower CI exceeded j3.0 and equivalence between low- andheavy-load intensities could not be declared, favoring heavy-load resistance exercise.
Interarm volume percent difference. Equivalence be-tween intensities was observed at all time points for interarmvolume percent differences, as estimated mean differences and90% CI were within the T3.0 margin of equivalence (Table 4).
BCRL symptoms. Equivalence between resistance exer-cise intensities was found for all BCRL symptoms at all timepoints, as estimated mean differences and associated 90% CIwere within the equivalence margin of T1.0 (Table 4).
No adverse events related to exercise (i.e., sprains orstrains) were reported. However, two (11%) participants wereadvised to seek evaluation by a lymphedema therapist at theend of the study period because L-Dex scores had exceeded10 (Fig. 2A). One participant had a preexercise L-Dex scoreof 7.9 in week 1. Upon instigating the low-load session atweek 2, an L-Dex score of 11.7 was observed, with subse-quent measures decreasing. The other participant initiated theheavy-load session at week 1 with a preexercise L-Dex scoreof 3.8, and subsequent measures fluctuating less than 5.0 units.At week 2, a preexercise L-Dex score of 9.5 was observed thatincreased to 12.7 after exercise, with decreasing subsequentmeasures. Notably, this participant suffered from rapid weightgain due to generalized edema between weeks 1 and 2 that waseffectively treated with diuretics. All other outcomes werewithin the predetermined clinical thresholds at all time pointsfor both of these participants.
DISCUSSION
The findings of this study support the hypothesis that acutechanges in extracellular fluid, arm volume, and BCRL-relatedsymptoms were similar irrespective of whether low- orheavy-load upper-extremity resistance exercise was performedduring adjuvant taxane-based chemotherapy in women withaxillary lymph node dissection.
This is the first study to prospectively investigate lym-phatic response to resistance exercise with heavy loads
TABLE 1. Baseline characteristics of participants (n = 21).
Variables Mean T SD/Median (Range)
Age, yr 45.3 T 9.2/46 (23–60)BMI, kgImj2 25.3 T 4.7Cancer stage, n (%)
II 15 (71)III 6 (29)
Tumor size, mm 21.5 T 12.9/18 (7–62)Breast surgery, n (%)
Lumpectomy 8 (38)Mastectomy 13 (62)
Surgery on dominant side, n (%) 11 (52)Axillary lymph nodes removed 21.7 T 7.8Metastatic lymph nodesa 5.7 T 7/2 (1–25)Seroma drainage 5.5 T 3.4Chemotherapy, n (%)
3-wk CE � 3 Y 3-wk docetaxel � 3 10 (48)3-wk CE � 3 Y 1-wk paclitaxel � 9 11 (52)
Axillary webbing at screening, n (%) 8 (38)L-Dex at screening j0.08 T 2.23
aMicrometastase and macrometastase.CE, cyclophosphamide and epirubicin.
HEAVY-LOAD RESISTANCE EXERCISE AND LYMPHEDEMA Medicine & Science in Sports & Exercised 191
CLIN
ICALSC
IENCES
(85%–90% 1RM, for 5–8 repetitions) in breast cancer sur-vivors at risk for developing BCRL. Findings are consistentwith observations from a cross-sectional study (n = 149) thatshowed no association between participation in a multi-modal exercise intervention including heavy-load resistanceexercise during taxane-based chemotherapy and BCRL de-velopment (30). Furthermore, our results are consistent withthe findings of Cormie et al. (16), demonstrating that par-ticipation in a bout of resistance exercise using 6–10RM
loads did not acutely exacerbate swelling or BCRL symp-toms in women with stable lymphedema. As such, this lendscredibility to the results of the present study.
The equivalence design was considered the most appro-priate for addressing our research question and was formal-ized by defining equivalence margins for all outcomes.Equivalence margins ideally represent the maximum clini-cally acceptable difference that one is willing to accept inreturn for the secondary benefits of a new therapy (27),
FIGURE 2—Individual response related to low- and heavy-load resistance exercise sessions for all outcomes (n = 17). A, Heavy-load L-Dex pre-, post-,and 24 h (n = 18). In subplots C–F, heavy-load breast cancer–related lymphedema symptoms preexercise and postexercise (n = 18). n refers to thenumber of participants with a symptom score of 0 at all time points.
http://www.acsm-msse.org192 Official Journal of the American College of Sports Medicine
CLINICALSC
IENCES
which in this study was heavy-load resistance exercise. Thevalue and impact of establishing equivalence depend on howwell the equivalence margin can be justified in terms ofrelevant evidence and clinical judgment, where a narrowerequivalence margin makes it more difficult to establishequivalence (27). The equivalence margin for the primaryoutcome was estimated as 3.0 L-Dex units. A priori, thethreshold was chosen on the basis of change scores consid-ered to be clinically relevant for persons with BCRL, be-cause no known normative change scores existed for personswithout BCRL. However, new normative data recentlypublished indicate that L-Dex scores fluctuate between 9and 11 units (31). This is in line with our results, finding that16 (89%) participants experienced deviations from the pre-determined L-Dex threshold. As such, although the equi-valence margin for this outcome likely was unnecessarilynarrow, this adds confidence to our findings. Furthermore,had we used broader L-Dex equivalence margins, the 90% CI
at 72 h after exercise would have fallen within the margin ofequivalence. Therefore, in light of these new normative data,it is likely that response to resistance exercise intensities wasequivalent at all time points.
Equivalence was also established for all assessed BCRLsymptoms at all time points, and although fluctuations be-yond the predetermined thresholds were observed, it shouldbe highlighted that the majority (82%) of these deviationsindicated reductions in severity after resistance exercise withboth intensities. This is relevant because symptoms can bethe earliest indicator of an ensuing BCRL (32).
When interpreting the findings, several limitations shouldbe considered. In this study, participants were excluded ifthey presented with evidence of BCRL according to stan-dardized protocols for BIS (L-Dex 910) or visual inspection.It is, however, possible that these women were experiencingtransient increases in extracellular fluid, either as a conse-quence of surgery or in response to chemotherapy (33), and/ormay have been at greatest risk for developing BCRL. Assuch, these women may have been more likely than thoseincluded in the study to demonstrate changes in extracellularfluid, and by excluding them, it may have been easier to findequivalence between loads. Moreover, activities undertakenby participants within the 3 d after the bout of low- or high-load resistance may have influenced data collected at 24 or72 h post–exercise session. However, participants were ad-vised to maintain normal activities throughout the studyperiod, and efforts were made to standardize treatment bur-den by placing exercise bouts and consecutive data collec-tions between chemotherapy cycles.
Strengths of this study include that all participants had re-ceived axillary node dissection, considered the largest singlerisk factor for developing BCRL, lending generalizability to
TABLE 4. Equivalence between resistance exercise intensities for all outcomes (n = 17).
Estimated Mean Differenceb Equivalence 90% CI
L-Dex (T3.0)a
Postexercise j0.97 j2.09 to 0.1624 h postexercise j0.14 j1.63 to 1.3572 h postexercise j1.00 j3.17 to 1.17
Interarm volume % difference (T3.0)a
Postexercise 0.21 j0.89 to 1.3124 h Postexercise 1.09 0.41 to 1.7872 h Postexercise 0.96 j0.09 to 2.02
Interarm difference for pain (T1.0)a
Postexercise 0 j0.43 to 0.4324 h postexercise j0.06 j0.58 to 0.4672 h postexercise j0.06 j0.61 to 0.49
Interarm difference for heaviness (T1.0)a
Postexercise 0.24 j0.23 to 0.7024 h postexercise 0.18 j0.32 to 0.6772 h postexercise 0.24 j0.38 to 0.85
Interarm difference for tightness (T1.0)a
Postexercise j0.06 j0.45 to 0.3424 h postexercise j0.11 j0.50 to 0.2772 h postexercise 0.20 j0.37 to 0.77
Interarm difference for swelling (T1.0)a
Postexercise 0 j0.33 to 0.3324 h postexercise 0 j0.33 to 0.3372 h postexercise 0.06 j0.42 to 0.54
Boldface indicates that equivalence was not demonstrated.aEquivalence margin.bEstimated mean difference calculated using a GEE model with heavy load as comparator(heavy minus low).
TABLE 2. Number (%) of participants exceeding equivalence margin from preexercise toimmediately postexercise and 24 and 72 h after exercise for all outcomes (n = 17).
¸ Pre–Post ¸ Pre–24 h Post ¸ Pre–72 h Post
L-DexHeavy load 2j (11%)a 2, (11%)a 2j (12%), 3, (18%)Low load 4j (24%), 1, (6%) 3j (18%), 4, (24%) 4j (24%), 4, (24%)
% interarm differenceHeavy load 2j (12%) 1j (6%) 1j (6%)Low load 1, (6%) 0 1, (6%)
PainHeavy load 2, (11%)a 1j (6%), 2, (12%) 2, (12%)Low load 2, (12%) 1j (6%), 1, (6%) 1, (6%)
HeavinessHeavy load 1j (6%), 1, (6%)a 1, (6%) 2, (12%)Low load 2, (12%) 2, (12%) 2, (12%)
TightnessHeavy load 0a 1j (6%), 1, (6%) 1, (6%)Low load 1, (6%) 1, (6%) 2, (12%)
SwellingHeavy load 1j (6%), 1, (6%)a 1, (6%) 1, (6%)Low load 0 1, (24%) 2, (12%)
j, higher than equivalence margin; ,, lower than equivalence margin.an = 18.
TABLE 3. Extent of swelling and breast cancer–related lymphedema symptoms for alloutcomes (n = 17).
Preexercise Postexercise24 h
Postexercise72 h
Postexercise
L-Dex scoreHeavy load 1.7 T 3.3a 1.9 T 3.4a 1.0 T 2.6a 0.8 T 3.9Low load 0.8 T 5.0 1.9 T 5.1 0.2 T 4.4 0.7 T 3.6
% interarm differenceHeavy load 0.5 T 4.4 1.0 T 4.0 1.4 T 4.2 1.1 T 4.3Low load 1.3 T 4.1 1.6 T 4.8 1.0 T 4.2 0.8 T 4.4
PainHeavy load 0 (j1, 6)a 0 (j1, 2)a 0 (j1, 3) 0 (0, 2)Low load 0 (0, 5) 0 (j1, 1) 0 (j1, 2) 0 (j1, 4)
HeavinessHeavy load 0 (0, 2)a 0 (0, 4)a 0 (0, 2) 0 (0, 2)Low load 0 (0, 5) 0 (0, 3) 0 (0, 2) 0 (0, 2)
TightnessHeavy load 0 (0, 6)a 0 (0, 5)a 0 (0, 3) 0 (0, 3)Low load 0 (0, 7) 0 (0, 8) 0 (0, 8) 0 (0, 3)
SwellingHeavy load 0 (0, 2)a 0 (0, 3)a 0 (0, 2) 0 (0, 2)Low load 0 (0, 2) 0 (j1, 3) 0 (0, 2) 0 (0, 2)
L-Dex and interarm volume presented as mean T SD. BCRL-related symptoms presentedas median (range).an = 18.
HEAVY-LOAD RESISTANCE EXERCISE AND LYMPHEDEMA Medicine & Science in Sports & Exercised 193
CLIN
ICALSC
IENCES
breast cancer survivors at BCRL risk. Furthermore, becauseall exercise sessions took place during the taxane-based cy-cles of chemotherapy, the results extend to acute bouts oflow- or high-load resistance-type activities during taxane-based treatment. Finally, validated objective measurementmethods sensitive to changes in extracellular fluid were used,and all data collections and analyses were blinded to resis-tance load lending credibility to the results.
Findings from this study are clinically relevant for anumber of reasons. First, the safety of resistance exercise inregard to BCRL risk has previously been established on thebasis of exercise prescription using low- to moderate loads.For example, some resistance exercise programs started withlittle or no weight and slowly progressed with the smallestweight increment possible until loads lifted corresponded toweights that successfully could be lifted a minimum of 15repetitions (12) or within a range of 10–12 repetitions (34),whereas others used loads corresponding to 60%–80% 1RMat 8–12 repetitions (10,13). As such, this work adds newinformation, providing initial evidence that resistance exer-cise prescription also can include heavier loads, specificallycorresponding to 85%–90% 1RM at 5–8 repetitions.
Second, a considerable rationale exists for participatingin resistance exercise during chemotherapy because it hasbeen found to elicit increases in muscle strength (10,35,36),lean body mass (10), and self-esteem (10) as well as at-tenuating fatigue and quality of life (36). Moreover, it hasbeen hypothesized that resistance exercise reduces taxane-related edema (37) through the effects of the muscle pump,and it is plausible that participation in heavy-load resistanceexercise may instigate more effective lymphatic functionchange than low-load resistance exercise, and in doing so,potentially have a greater effect on reducing BCRL risk. Assuch, results from this study provide the necessary platformfor future studies to explore whether additional benefits canbe gained from repeated bouts of heavy-load resistance
exercise during adjuvant taxane-based chemotherapy. Fi-nally, breast cancer survivors commonly receive risk re-duction advice cautioning against heavy lifting (38). Thisstudy, however, found no evidence to suggest that partici-pation in activities of daily living that include intermittentheavy-load lifting need be avoided. Furthermore, a variedresponse to resistance exercise was observed for both in-tensities. This highlights the importance of an individualizedapproach to resistance exercise prescribed in accordancewith signs and symptoms of BCRL, as well as an individu-alized approach to the risk reduction advice given to breastcancer survivors.
In conclusion, the acute lymphatic response was similarirrespective of whether low- or heavy-load resistance exer-cise was undertaken in women with axillary node dissectionat risk for BCRL during adjuvant taxane-based chemother-apy. Future research needs to now investigate the longer-term response to regular heavy-load resistance exercise. Inthe interim, these findings challenge existing risk reductionadvice concerning avoidance of heavy lifting and suggestthat breast cancer survivors should be encouraged to par-ticipate in normal daily activities and to act accordingly ifchanges in sensations or BCRL symptoms are observed.
We gratefully acknowledge exercise physiologists ChristianLillelund for his input in the conception of the study and JesperChristensen for his assistance with the random allocation of partici-pants. Also thanks to staff at the Department of Clinical Physiologyand Nuclear Medicine at the Copenhagen University Hospital,Rigshospitalet, for excellent data collection and the CopenhagenCentre for Cancer and Health for help in recruitment. Lastly, thanksto the participants for dedicating time and energy and making thestudy possible.
This study was funded by the University Hospitals Centre for HealthResearch (UCSF), Copenhagen University Hospital, Rigshospitalet.The authors declare no conflict of interest. The results of the study arepresented clearly, honestly, and without fabrication, falsification, orinappropriate data manipulation and do not constitute endorsementby the American College of Sports Medicine.
REFERENCES
1. DiSipio T, Rye S, Newman B, Hayes S. Incidence of unilateral armlymphoedema after breast cancer: a systematic review and meta-analysis. Lancet Oncol. 2013;14(6):500–15.
2. Cheville AL, McGarvey CL, Petrek JA, Russo SA, Thiadens SR,Taylor ME. The grading of lymphedema in oncology clinical trials.Semin Radiat Oncol. 2003;13(3):214–25.
3. Boyages J, Kalfa S, Xu Y, et al. Worse and worse off: the impact oflymphedema on work and career after breast cancer. Springerplus.2016;5:657.
4. Morgan PA, Franks PJ, Moffatt CJ. Health-related quality of life withlymphoedema: a review of the literature. Int Wound J. 2005;2(1):47–62.
5. Fu MR, Ridner SH, Hu SH, Stewart BR, Cormier JN, Armer JM.Psychosocial impact of lymphedema: a systematic review of lit-erature from 2004 to 2011. Psychooncology. 2013;22(7):1466–84.
6. Cheema BS, Kilbreath SL, Fahey PP, Delaney GP, Atlantis E.Safety and efficacy of progressive resistance training in breastcancer: a systematic review and meta-analysis. Breast Cancer ResTreat. 2014;148(2):249–68.
7. Paramanandam VS, Roberts D. Weight training is not harmful forwomen with breast cancer–related lymphoedema: a systematic re-view. J Physiother. 2014;60(3):136–43.
8. Keilani M, Hasenoehrl T, Neubauer M, Crevenna R. Resistanceexercise and secondary lymphedema in breast cancer survivors—asystematic review. Support Care Cancer. 2016;24(4):1907–16.
9. Nelson NL. Breast cancer–related lymphedema and resistanceexercise: a systematic review. J Strength Cond Res. 2016;30(9):2656–65.
10. Courneya KS, Segal RJ, Mackey JR, et al. Effects of aerobic andresistance exercise in breast cancer patients receiving adjuvantchemotherapy: a multicenter randomized controlled trial. J ClinOncol. 2007;25(28):4396–404.
11. Swaroop MN, Ferguson CM, Horick NK, et al. Impact of adjuvanttaxane-based chemotherapy on development of breast cancer–relatedlymphedema: results from a large prospective cohort. Breast CancerRes Treat. 2015;151(2):393–403.
12. Sagen A, Karesen R, Risberg MA. Physical activity for the af-fected limb and arm lymphedema after breast cancer surgery. Aprospective, randomized controlled trial with two years follow-up.Acta Oncol. 2009;48(8):1102–10.
13. Simonavice E, Kim JS, Panton L. Effects of resistance exercise inwomen with or at risk for breast cancer–related lymphedema.Support Care Cancer. 2017;25(1):9–15.
http://www.acsm-msse.org194 Official Journal of the American College of Sports Medicine
CLINICALSC
IENCES
14. American College of Sports Medicine. American College of SportsMedicine Position Stand. Progression models in resistance trainingfor healthy adults. Med Sci Sports Exerc. 2009;41(3):687–708.
15. Csapo R, Alegre LM. Effects of resistance training with moderatevs heavy loads on muscle mass and strength in the elderly: a meta-analysis. Scand J Med Sci Sports. 2016;26(9):995–1006.
16. Cormie P, Galvao DA, Spry N, Newton RU. Neither heavy norlight load resistance exercise acutely exacerbates lymphedema inbreast cancer survivor. Integr Cancer Ther. 2013;12(5):423–32.
17. Cormie P, Pumpa K, Galvao DA, et al. Is it safe and efficacious forwomen with lymphedema secondary to breast cancer to lift heavyweights during exercise: a randomised controlled trial. J CancerSurviv. 2013;7(3):413–24.
18. Bloomquist K, Hayes S, Adamsen L, et al. A randomized cross-overtrial to detect differences in arm volume after low- and heavy-loadresistance exercise among patients receiving adjuvant chemotherapyfor breast cancer at risk for arm lymphedema: study protocol. BMCCancer. 2016;16:517.
19. Adamsen L, Quist M, Andersen C, et al. Effect of a multimodalhigh intensity exercise intervention in cancer patients undergoingchemotherapy: randomised controlled trial. BMJ. 2009;339:b3410.
20. Ward LC, Dylke E, Czerniec S, Isenring E, Kilbreath SL. Confir-mation of the reference impedance ratios used for assessment ofbreast cancer–related lymphedema by bioelectrical impedancespectroscopy. Lymphat Res Biol. 2011;9(1):47–51.
21. Cornish BH, Jacobs A, Thomas BJ, Ward LC. Optimizing elec-trode sites for segmental bioimpedance measurements. PhysiolMeas. 1999;20(3):241–50.
22. Gjorup C, Zerahn B, Hendel HW. Assessment of volume mea-surement of breast cancer–related lymphedema by three methods:circumference measurement, water displacement, and dual energyx-ray absorptiometry. Lymphat Res Biol. 2010;8(2):111–9.
23. Hawker GA, Mian S, Kendzerska T, French M. Measures of adultpain: Visual Analog Scale for Pain (VAS Pain), Numeric RatingScale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ),Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic PainGrade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36BPS), and Measure of Intermittent and Constant OsteoarthritisPain (ICOAP). Arthritis Care Res (Hoboken). 2011;63(11 Suppl):S240–52.
24. Liang KY, Zeger SL. Longitudinal data analysis using generalizedlinear models. Biometrika. 1986;73:13–22.
25. Westlake WJ. Use of confidence intervals in analysis of compar-ative bioavailability trials. J Pharm Sci. 1972;61(8):1340–1.
26. Stout Gergich NL, Pfalzer LA, McGarvey C, Springer B, GerberLH, Soballe P. Preoperative assessment enables the early diagnosisand successful treatment of lymphedema. Cancer. 2008;112(12):2809–19.
27. Walker E, Nowacki AS. Understanding equivalence and non-inferiority testing. J Gen Intern Med. 2011;26(2):192–6.
28. Team RC. R: a language and environment for statistical comput-ing: R Foundation for Statistical Computing; 2015 [cited Feb2017]. Available from: https://www.R-project.org/.
29. Halekoh UHS, Yan J. The R package geepack for generalized es-timating equations. J Stat Softw. 2006;15(2):1–11.
30. Bloomquist K, Karlsmark T, Christensen KB, Adamsen L. Heavyresistance training and lymphedema: prevalence of breast cancer–related lymphedema in participants of an exercise intervention uti-lizing heavy load resistance training. Acta Oncol. 2014;53(2):216–25.
31. Hayes S, Janda M, Steele M, et al. Identifying diagnostic criteriafor upper- and lower-limb lymphoedema Impedimed Limited:Queensland University of Technology Faculty of Health, School ofPublic Health and Social Work and Institute of Health and Bio-medical Innovation; 2016 [updated 3 July 2017; cited 31 May 2017 ].Available from: https://eprints.qut.edu.au/view/person/Hayes,_Sandra.html#group_report.
32. Fu MR, Axelrod D, Cleland CM, et al. Symptom report indetecting breast cancer–related lymphedema. Breast Cancer (DoveMed Press). 2015;7:345–52.
33. Kilbreath SL, Lee MJ, Refshauge KM, et al. Transient swellingversus lymphoedema in the first year following surgery for breastcancer. Support Care Cancer. 2013;21(8):2207–15.
34. Schmitz KH, Ahmed RL, Troxel AB, et al. Weight lifting forwomen at risk for breast cancer–related lymphedema: a random-ized trial. JAMA. 2010;304(24):2699–705.
35. Schwartz AL, Winters-Stone K, Gallucci B. Exercise effects onbone mineral density in women with breast cancer receiving ad-juvant chemotherapy. Oncol Nurs Forum. 2007;34(3):627–33.
36. Schmidt ME, Wiskemann J, Armbrust P, Schneeweiss A, Ulrich CM,Steindorf K. Effects of resistance exercise on fatigue and quality oflife in breast cancer patients undergoing adjuvant chemotherapy: arandomized controlled trial. Int J Cancer. 2015;137(2):471–80.
37. Lane K, Worsley D, McKenzie D. Exercise and the lymphaticsystem: implications for breast-cancer survivors. Sports Med. 2005;35(6):461–71.
38. McLaughlin SA, Bagaria S, Gibson T, et al. Trends in risk reductionpractices for the prevention of lymphedema in the first 12 monthsafter breast cancer surgery. J Am Coll Surg. 2013;216(3):380–9.
HEAVY-LOAD RESISTANCE EXERCISE AND LYMPHEDEMA Medicine & Science in Sports & Exercised 195
CLIN
ICALSC
IENCES
Paper IV
1
Heavy-load resistance exercise in pre-diagnosis, physically inactive
women at risk of breast cancer-related lymphedema during
adjuvant chemotherapy: a randomized trial
Kira Bloomquist1, Lis Adamsen1, Sandra C Hayes2, Christian Lillelund1,
Christina Andersen1, Karl Bang Christensen3, Peter Oturai4, Bent
Ejlertsen5, Malgorzata K Tuxen6, Tom Møller1
University Hospitals Centre for Health Research (UCSF), Copenhagen University Hospital, Copenhagen, Denmark
Corresponding author: Kira Bloomquist
University Hospitals Centre for Health Research, UCSF
Copenhagen University Hospital
Blegdamsvej 9
2100 Copenhagen, Denmark
E-mail: [email protected]
Telephone: +45 35457362
1University Hospitals Centre for Health Research (UCSF), Copenhagen University
Hospital, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark, (LA) + 45 35457338,
[email protected]; (CL) +45 35457335, [email protected]; (CA) +45
35457388, [email protected]; (TM) +4535457366,
[email protected]; 2Institute of Health and Biomedical Innovation, School of Public Health and Social
Work, Queensland University of Technology, Victoria Park Road, , Kelvin Grove,
4059, Queensland, Australia, +61 31389645, [email protected] 3Department of Public Health; Section of Biostatistics, University of Copenhagen,
Øster Farimagsgade 5, 1014 Copenhagen K, Denmark, +45 35327491,
2
4Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen
University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark,+45 3545 9665,
[email protected] 5DBCG, Afsnit 2501, Copenhagen University Hospital, Blegdamsvej 9, 2100
Copenhagen Ø, Denmark, +45 35253417, [email protected] 6Oncology department, Team MA, Herlev Hospital, Herlev Ringvej, 2730 Herlev,
Denmark, +45 35454090, [email protected]
3
Heavy-load resistance exercise in pre-diagnosis physically inactive women at risk of
breast cancer-related lymphedema during adjuvant chemotherapy: a randomized trial
Abstract
Background
It is unclear whether participating in heavy-load resistance exercise is safe for breast
cancer survivors considered at risk of developing lymphedema. This study
prospectively evaluated changes in lymphedema outcomes following participation in
repeated exposure to heavy-load resistance exercise during adjuvant chemotherapy in
physically inactive women with breast cancer.
Material and Methods
This is a parallel group, randomized trial. Screened pre-diagnosis physically
inactive women receiving adjuvant chemotherapy for breast cancer (n=153)
participated in 12 weeks of 1) HIGH: supervised multimodal exercise
including heavy-load resistance exercise (85-90% 1 repetition maximum (RM),
three sets of 5-8 repetitions) or 2) LOW: walking supported by pedometer and
one-on-one consultations. Outcomes: swelling (bioimpedance spectroscopy, L-
Dex scores; dual energy X-ray absorptiometry, inter-arm volume % difference;
self-report, n %), lymphedema symptoms (0-10 rating scale), upper-extremity
strength (1 RM), and self-reported function and symptoms (EORTC breast
cancer-specific questionnaire (BR23)), assessed at baseline, 12 and 39 weeks.
Linear mixed models with a heterogeneous autoregressive (1) covariance
structure were used to evaluate changes over time between groups.
Equivalence was hypothesized for lymphedema outcomes, and was determined
using the principle of confidence interval inclusion.
4
Results
Post-intervention equivalence between groups was found for L-Dex and self-reported
heaviness, tightness and swelling. Non-equivalence was determined for inter-arm
volume and pain, as deviations beyond equivalence margins indicated reductions
associated with participation in the HIGH intervention for these two outcomes.
Further, greater increases (p < 0.05) in upper-extremity strength were seen in the
HIGH group compared to LOW at all assessments, and within group reductions in
breast and arm symptoms were observed in the HIGH group at 6 and 12 weeks.
Conclusion
This study indicates that pre-diagnosis physically inactive women considered at risk
of lymphedema during adjuvant chemotherapy for breast cancer can benefit from
heavy-load resistance exercise without adversely influencing lymphedema outcomes.
Trial registration: ISRCTN24901641.
Keywords: arm swelling; breast cancer; strength training; rehabilitation
Word count:4,661
5
Introduction
Breast cancer-related arm lymphedema (BCRL) is a chronic condition characterized
by swelling of the arm on the surgical side, experienced by almost a quarter of breast
cancer survivors and has adverse physical, social and psychological ramifications (1-
4). Since the pathophysiology of BCRL remains unclear, efforts to predict who will
develop BCRL are limited (5). Nonetheless, consistent evidence supports several risk
factors including more extensive surgery (mastectomy and axillary lymph node
dissection and greater number of lymph nodes removed), receipt of adjuvant
therapies (chemotherapy and radiotherapy) and lifestyle-related factors such as
obesity and physical inactivity (1).
Receipt of adjuvant chemotherapy for breast cancer is associated with
declines in physical activity (6). This in turn contributes to common increases in
body weight (7-10) characterized by no change or decline in muscle mass in the
presence of increased body fat (sarcopenic obesity) (7), and is adversely associated
with reductions in muscle strength and functional impairment (11, 12). Therefore,
interventions that thwart sarcopenic obesity are pertinent, with heavy-load resistance-
exercise considered an effective strategy. This is due to the dose-response
relationship that exists between resistance exercise and lean tissue, whereby heavier
loads have been shown to elicit greater gains in muscular size, structure and function
than with lower loads (13, 14).
However, there are anecdotal concerns that resistance exercise with heavy
loads may trigger the development of BCRL. While previous interventions have
demonstrated the safety of resistance exercise of low to moderate loads (60-80% of 1
repetition maximum (RM) or 8-20 RM) (15-18), only the acute response to heavy-
6
load resistance exercise has been evaluated in those at risk of developing BCRL.
Specifically, a recent study found that the acute lymphatic response was similar after
a single bout of low-and heavy-load resistance exercise in at -risk women (n = 21)
(19). While providing important preliminary information, the safety of repeated
exposure to heavy-load resistance exercise has yet to be examined in this particular
cohort.
Therefore, we prospectively compared the effect of a supervised, multimodal
intervention including heavy-load resistance exercise (80-90% 1 RM or 5-8 RM)
with a home-based individual walking intervention in pre-diagnosis physically
inactive breast cancer survivors during adjuvant chemotherapy. A full report
detailing the results on aerobic capacity (the primary outcome), body composition
and quality of life can be viewed elsewhere (ISRCTN24901641). The primary
purpose of this manuscript is to report on the effect of the interventions on BCRL
and upper-extremity outcomes. We hypothesized that changes in BCRL outcomes
would be similar irrespective of intervention allocation. Further, we hypothesized
that participation in the multimodal intervention would yield significant increases in
upper-extremity muscular strength and breast cancer-specific functional and
symptom domains compared to the walking intervention.
Material and Methods
This study utilized a parallel group, randomized design (n=153; detailed description
of study design and methods have been previously reported) (20, 21). The study was
conducted at the University Hospitals Centre for Health Research, Copenhagen
University Hospital, Rigshospitalet. Written informed consent was provided by all
participants before inclusion to the study. The study was approved by the Danish
7
Capital Regional Ethics Committee (H-1-2011-131) and the Danish Data Protection
Agency (2011-41-6349) and registered at Current Controlled Trials
(ISRCTN24901641).
Participants
Women referred to adjuvant chemotherapy for stage I-III breast cancer at the
oncology departments of The Copenhagen University Hospital, Rigshospitalet (RH)
and Herlev Hospital (HE) were screened for eligibility by nurses / physicians upon
initiation of chemotherapy. Women were eligible if they had a World Health
Organization performance status 0-1, and retrospectively rated their physical activity
levels three months prior to diagnosis as less than 150 minutes of regular, moderate-
intensity physical activity and / or 2 x 20 minutes of high-intensity exercise per week
(22). If initial criteria were met, women were then referred to the research team and
matched against exclusion criteria (diagnosed acute coronary heart syndrome within
the past six months, symptomatic heart disease, pathological echocardiogram,
contraindication for exercise noted in medical records, unable to read or understand
Danish). Participant flow in the study is presented in Figure 1.
Randomization
After successful completion of all baseline assessments (6-9 weeks post-surgery),
women were sequentially numbered and stratified by age (<48/48+ years) and
hospital (RH/HE). Intervention allocation (1:1) was determined by a computerized,
random number generated at the Copenhagen Trial Unit, which is an external clinical
research unit.
8
Guidelines regarding BCRL
Participants were asked if they had received treatment for BCRL at the baseline
assessment, either preventatively or as a means to reduce swelling after a diagnosis
of BCRL, and were given verbal and written information, highlighting current
evidence-based risk factors for developing BCRL (e.g. lymph node removal, BMI,
physical inactivity). Participants were encouraged to contact study personnel if signs
or symptoms of BCRL development (e.g. sensations of heaviness/tightness or visible
signs of swelling) presented or exacerbation of an existing BCRL occurred during
the study period. Either scenario would then instigate referral to a lymphedema
therapist for evaluation and treatment.
Interventions
HIGH
Participants randomized to the HIGH group participated in a twelve-week, group-
based exercise program, supervised by a cancer nurse specialist and a physical
therapist / exercise physiologist. The first six weeks consisted of a previously
described exercise program ‘Body and Cancer’ (20, 23, 24), which entailed
multimodal sessions including low-intensity and high-intensity components. The
following six weeks consisted of an ‘All sport’ exercise program focusing on high-
intensity components combined with other aerobic activities performed at moderate
to high intensities. (Table 1) (20). The high-intensity component included an aerobic-
based warm-up followed by resistance exercise and 15-30 minutes of cardiovascular
interval training on stationary bikes with peak loads equivalent to 85-95% maximal
heart rate. The resistance exercise program comprised of six machine-based
exercises (Technogym®, Gamettola, Italy) targeting major muscle groups of the body
9
(chest press, latissimus pull down, abdominal crunch, back extension, leg press and
knee extension). Resistance exercise loads were based on a 1 RM strength test for
each exercise. During the first week participants were instructed to lift loads
corresponding to 2-3 sets of 8-12 repetitions at 70% 1 RM, progressing to 80% 1 RM
in week two. From week three forward, loads lifted corresponded to 3 sets of 5-8
repetitions at 80-90% 1 RM. To ensure progression, resistance exercise programs
were adjusted every third week based on new 1 RM testing.
Pre-exercise screening was performed prior to all high-intensity exercise
sessions, with subsequent modified exercise intensity or omission from high-
intensity activities that day if criteria were not met (e.g., resting heart rate >100 beats
per minute, temp > 38o C) (20, 23). If participants developed signs of BCRL or
experienced exacerbations of an existing BCRL, they were instructed to refrain from
resistance exercise targeting the upper-extremities or to decrease loads, and were
referred to a lymphedema therapist.
LOW
The LOW intervention involved an individualized, home-based walking program
supported by a pedometer and one-on-one consultations with a cancer nurse
specialist or physical therapist (Table 1). Participants were issued an Omron Walking
Style Pro pedometer at baseline, and were encouraged to progressively increase steps
and ultimately to achieve 10,000 steps per day. Consultations were regularly held to
discuss daily walking targets and barriers and motivators for achieving these targets.
Beyond walking, participants were encouraged to exercise and to integrate physical
activity into activities of daily living.
10
Both interventions provided health promotion counselling (20) including
clinical advice concerning symptom management and feedback regarding
physiological outcomes.
Outcomes
BCRL was objectively assessed (inter-arm volume % difference and L-Dex) at
baseline, 12 and 39 weeks, by medical technicians at the Department of Clinical
Physiology and Nuclear Medicine, Rigshospitalet. Muscle strength and self-reported
outcomes were obtained by research assistants at the University Hospitals Centre for
Health Research, Rigshospitalet at baseline, 6, 12 and 39 weeks.
Inter-arm volume % difference
Arm volume was obtained using Dual energy X-ray absorptiometry (DXA) (Lunar
Prodigy Advanced Scanner, GE Healthcare, Madison, WI). DXA provides a
sensitive measure of tissue composition using a three-compartment model (25, 26).
Lying supine on the scan-table with arms slightly abducted and hands in a mid-prone
position, total body scans were performed. Scans were automatically point typed and
analyzed using encore version 16, GE Healthcare Lunar software. From the total
body scans, the measured weight of fat, lean mass and bone mineral content of both
arms were identified and converted into estimated arm volumes using previously
derived densities (fat - 0.9 g/ml, lean mass -1.1g/ml, bone mineral content - 1.85
g/ml)) with the region of interest extending from the gleno-humeral joint to the
finger tips (25, 26). Inter-arm volume % differences (at-risk arm minus unaffected
arm/unaffected arm * 100) were then calculated for each participant. To ensure
accuracy, participants were scanned fasting at the same time of day (mornings) at all
assessments.
11
L-Dex
Bioimpedance spectroscopy (BIS) (SFB7, Impedimed, Brisbane, Australia) was
performed immediately after the DXA scans. This measurement method directly
measures and compares the impedance of extracellular fluid in the upper-extremities
to electrical currents at a range of frequencies according to the manufacturer’s
software (27). Participants were positioned in supine with arms and legs slightly
abducted with palms facing down. Using the principle of equipotentials, four single-
tab electrodes were placed in a tetrapolar arrangement. Measurement electrodes were
placed on the dorsum of the wrist midway between the styloid processes. Current
drive electrodes were placed five centimeters distally on the dorsal side over the third
metacarpal of the hand, and midway on the third metatarsal on the dorsum of the foot
(28). The ratio of impedance (at R0) between the at-risk and non-affected arm was
calculated and converted into an L-Dex score taking arm dominance into account
(29). BIS data were consecutively obtained from participant 71 forward.
Self-reported swelling
Participants were asked if they had observed a difference in size between their
surgical-and non-surgical side within the last week (dichotomous scale- yes/no). If
they answered yes, they were then asked to report where (fingers, hand, forearm,
upper arm, breast, torso). For the purpose of binary analysis, categories were divided
into “extremity” (fingers, hand, forearm, upper arm) and “body” (breast, torso).
Self-reported BCRL symptoms
The severity of lymphedema symptoms on the surgical side was monitored using a
numeric rating scale (NRS)(30). Participants rated perceptions of swelling,
12
heaviness, pain and tightness within the last week on a scale from 0 (no discomfort)
to 10 (very severe discomfort)(31).
Upper-extremity muscular strength
To assess maximal strength of the upper extremity, the 1 RM strength test (32) was
performed using the chest press exercise. The 1 RM is the maximum amount of
weight that can be lifted for one repetition while maintaining proper technique. Prior
to the 1 RM attempt, a warm-up consisting of 8-10 repetitions using a low weight
ensuring no muscle fatigue occurred was performed. Hereafter, load was increased
based on ease of performance, with one repetition lifted of each load, until the
participant was unable to lift a respective load.
Breast cancer-specific functional and symptom domains
The 23 item European Organization for Research and Treatment of Cancer (EORTC)
breast cancer module (BR23)(33), version 3.0, was used to assess breast cancer-
specific quality of life issues. This validated breast cancer-specific module includes
four functional scales (body image, sexual functioning, sexual enjoyment, future
perspective), as well as four symptom specific subscales (systemic therapy side
effects, breast symptoms, arm symptoms, upset by hair loss). Each item is scored on
a four point Likert scale from “not at all” to “very much”. The raw scores were
summed and converted to a score out of 100, with higher levels of functioning
represented by higher functional scores and worse symptoms represented by higher
symptom scores (33, 34).
Blinding
Inherent to exercise studies, patients, nurses and physical therapist delivering the
interventions were aware of the allocated arm. However, all data collection and
13
subsequent data entry were performed blinded to group allocation by study assessors.
Further, all data analyses were performed with no knowledge of group allocation by
a statistician with no other affiliation to the study.
Statistical Analysis
Descriptive statistics included means ± SD for normally distributed variables or
median with interquartile range (IQR) for continuous variables. Categorical variables
as well as BCRL point prevalence defined as L-Dex >10, inter-arm volume
difference >5%, self-reported observation of swelling, respectively are presented as
counts (percentages). Intention-to-treat analyses were performed using linear mixed
models with a heterogeneous autoregressive (1) covariance structure to estimate
changes over time in each group. An exchangeable correlation structure was used to
model the within-subject correlation of repeated measurements over time and across
interventions. This incorporates all available data including participants with
incomplete data. Also, effect sizes were calculated for muscular strength (35). A
two-sided significance level was set at 0.05 for outcomes where superiority was
hypothesized (muscular strength and breast cancer-specific functional and symptom
domains).
A priori, clinically relevant equivalence margins were chosen for BCRL
outcomes. If the interval between the upper- and lower- confidence limits was within
the predetermined equivalence margin, equivalence between interventions was
declared (36). An equivalence margin of ±3.0% was used for inter-arm volume %
differences based on findings from Stout et al., (37) that volume increases of >3%
from pre-operative measures were indicative of sub-clinical BCRL. For L-Dex, the
margin of equivalence was set at ±5.0 units based on normative data indicating that
14
L-Dex scores fluctuate between 9-11 units (29). For lymphedema symptom severity
an equivalence margin was set at ±1.0 points. This threshold was based on data that
suggest a 2 point or 30% change to be clinically meaningful for pain (30). The
principle of confidence interval inclusion (38) was used to calculate two one-sided
upper- and lower-95% confidence limits for L-Dex, inter-arm volume % differences,
and BCRL symptom outcomes (reported as 90% confidence limits). A per-protocol
analysis was performed to determine equivalence of BCRL outcomes of participants
with an adherence rate >65% to the HIGH intervention (n = 33). Means and 90% CI
were calculated and compared with the predetermined equivalence margins.
Analyses were conducted using Statistical Analysis Software (SAS) version 9.4.
Results
Between January 2014 and July 2016, 153 of 391 (39%) eligible women receiving
adjuvant chemotherapy for breast cancer were recruited (Figure 1). Baseline
characteristics were balanced between the two intervention groups (Table 2).
For participants with and without L-Dex data, baseline characteristics were balanced
with the exception of chemotherapy regime, as more participants with L-Dex data
had received paclitaxel based chemotherapy (13 (20.3%) vs. 6 (6.7%, respectively).
Further, differences were seen in the mean BMI of participants with and without
inter-arm volume data as the body dimensions of some participants exceeded the
DXA scan area (24.3 ± 3.6 with DXA vs. 31.2 ± 5.2 without DXA).
Retention, adherence and adverse events
Outcome data were available for 130 participants (85%) at 12-weeks post-
intervention, and for 121 (79%) at the 39 week follow-up (Figure 1). On average,
participants in the HIGH group attended 66% (±18) of the planned exercise sessions.
15
Four women never partook in the intervention and an additional six withdrew shortly
after initiation of the program. A detailed description of reasons for non-attendance
can be found elsewhere (in submission). Adherence to resistance exercise
prescription of the upper-extremity corresponded to a median load of 10 RM during
the first two weeks. From week three forward (heavy-load period), loads
corresponded to 7 RM. Comparatively loads lifted for the leg press were 14 RM and
8 RM, respectively.
No exercise-related injuries were reported. Six participants (8%) in the HIGH
and five participants (6%) in the LOW group developed swelling during the 12-week
intervention and were referred to lymphedema therapists for evaluation and
treatment. Just one of the women in the HIGH group reduced loads (10-15 RM),
whereas the other five continued lifting loads corresponding to 5-8 RM. At 39
weeks, seven of these participants had received treatment for BCRL by a
lymphedema therapist following the intervention, while three had not, and one was
lost-to follow-up.
Lymphedema
Point prevalence: While point prevalence of BCRL varied depending on the method
of assessment (Table 3), it was similar between the HIGH and LOW group at all time
points, for any given method of assessment (Table 3).
Self-reported diagnosis of BCRL at baseline: Five participants (3.3%) reported at
baseline that they were receiving treatment for a diagnosed BCRL, all of whom also
reported observations of size difference between sides within the last week (Table 3).
One of these women had an L-Dex >10, accounting for one of two point prevalent
16
cases identified by BIS (Table 3). No L-Dex was available for three participants. In
regard to inter-arm volume, no DXA data were available for two women (body
dimensions exceeding scan area), and two others had swelling in the torso only
(DXA not able to detect). One of the five participants was in the HIGH group. This
woman continued treatment by a lymphedema therapist throughout the twelve-week
intervention and undertook the resistance exercise protocol without need for
modification (e.g. less load). At twelve weeks she reported no observations of
swelling along with reductions in symptoms. No DXA or BIS data were available.
Inter-arm volume % difference: Non-equivalence was observed at all time points for
inter-arm volume % differences with deviations exceeding equivalence margins
favoring the HIGH group (Table 4). These observations were consistent with
findings from the per-protocol analysis (Table 5).
L-Dex: The mean difference in L-Dex scores between the HIGH and LOW group
and associated two-sided 90% CIs were contained within the predetermined
equivalence margin of ±5.0 units at both 12 and 39 weeks indicating equivalence
between groups (Table 4). Equivalence to the predetermined equivalence margin in
the per-protocol analysis at 12 weeks was also observed (Table 5). However at the 39
week follow-up, the upper CI exceeded the predetermined margin of equivalence
(Table 5).
BCRL symptoms: Equivalence between groups was found in all symptoms except for
pain at the 12 week follow-up, and tightness and pain at the 39 week follow-up, with
17
all findings favoring reductions for those in the HIGH group (Table 4). Results of the
per-protocol analysis also indicated equivalence for heaviness and swelling post-
intervention and at the 39 week follow-up, as well as pain post-intervention (Table
5). However, non-equivalence was found for pain at the 39 week follow-up as upper
CI’s exceed the equivalence margin. Further, equivalence could not be determined
for tightness, as lower CI’s exceeded the equivalence margin at both follow-up time
points, as well the mean change at the 39 week follow-up.
Upper-extremity muscular strength
A significant change in maximal upper-extremity strength was observed for
participants in the HIGH group at all follow-up assessments (Table 6). At 6- and 12-
week follow-up, these strength increases were significantly greater compared to
those in the LOW group and corresponded to effect sizes of 0.55 (95% CI 0.40 –
0.75), 0.55 (0.35 – 0.70) and 0.35 (0.15 – 0.55) at the 6, 12 and 39 weeks follow-up,
respectively.
Breast cancer-specific functional and symptom domains
No between group differences were observed for any subscale score of the EORTC-
BR23 at all assessments (Table 4 and supplemental material). Nonetheless, both
groups reported declines in breast symptoms at 6 and 12 weeks follow-up and arm
symptoms at 6 weeks follow-up, while reductions in arm symptom at 12 weeks
follow-up was only seen in the HIGH group.
Discussion
This is the first study to prospectively evaluate the safety of repeated exposure to
heavy-load resistance exercise in breast cancer survivors at risk for BCRL. We found
no evidence suggesting that participating in a twelve-week multimodal exercise
18
intervention including heavy-load resistance exercise during chemotherapy increased
risk of developing BCRL. In line with the hypothesis, we found similar point
prevalent cases of BCRL between groups, as well as similar between group L-Dex
scores and perceptions of heaviness, swelling and tightness post-intervention.
Though equivalence was not demonstrated in inter-arm volume % differences or
self-reported pain, the negative deviations indicated reductions of these outcomes,
favoring the HIGH group. Notably, per-protocol analysis of HIGH participants with
>65% adherence consistently supported equivalence to- or reductions beyond the
predetermined equivalence margins, adding strength to the findings.
This work extends the results of previous research finding a similar acute
lymphatic response to one bout of low-and heavy-load resistance exercise (19), to
repeated exposure of resistance exercise with heavy loads. Further, our results are in
agreement with findings of Cormie et al. (31, 39) who demonstrated the safety of
heavy-load (75-85% of 1 RM using 6-10 RM) resistance exercise in breast cancer
survivors with stable BCRL. As such, these results add to a growing and consistent
evidence base which suggests that exercise is safe for those with or at-risk of
developing lymphedema (15-18), and includes participation in heavy-load resistance
exercise. Notably, the findings contributed to the broader literature by this work are
particularly relevant for the majority of breast cancer survivor who receive
chemotherapy as taxane-based chemotherapy is considered standard first line
treatment (40, 41), with generalized edema and ensuing arm swelling as a known
side-effect of this cytostatic agent (42).
19
No between group differences in breast and arm symptoms were found
between interventions, consistent with results from two previous studies (39, 43).
Kilbreath et al. (n = 160) found no difference in arm and breast symptoms between
women at risk of BCRL after eight weeks of resistance exercise using loads
corresponding to 8-15 RM, commencing 4-6 weeks post-surgery, and a control
group (43). Similarly, in women with stable BCRL, Cormie et al. (n =62) found no
difference in arm symptoms between two resistance exercise groups (heavy and low
load) and a control group (39). Notably however, though no differences between
groups were found, clinically relevant within group reductions in breast and arm
symptoms were found in the HIGH group (44) at both 6- and 12 weeks. These
findings are consistent with the BCRL results from the present study, adding strength
to the findings.
Participation in HIGH significantly improved upper-extremity strength
compared to the LOW intervention, with an effect size of 0.55 (95% CI 0.35-0.70)
post-intervention. These data are consistent with pooled estimates from a systematic
review (16) that included fifteen randomized controlled studies evaluating
populations with stable BCRL or at risk for developing BCRL. Findings from the
meta-analysis showed that participation in resistance exercise significantly increased
muscular strength compared to controls (effect size 0.57 (95% CI 0.37-0.76).
Further, upper-extremity strength increases corresponded to 17.24%, 13.33%, and
6.67% at 6, 12, and 39 weeks, respectively, for those in the HIGH group, compared
to a 3.33%, 3.33% and 3.44% increases in the LOW group. These are relevant
findings as upper-extremity strength in breast cancer survivors (without intervention)
has been found to be 12-16% lower compared to healthy women (45). As such, the
20
present study indicates that participation in heavy-load resistance exercise during
chemotherapy can mitigate declines in muscle strength, of importance for
recreational and daily living activities (46). Future studies should therefore explore
whether additional benefits can be gained from resistance exercise with heavier loads
during chemotherapy, as published results suggest superior efficacy in decreasing
fatigue (47) and rate of bone loss (48) and increasing lean body mass (49).
At 39 weeks follow-up, we found that the longer term effect of the LOW and
HIGH intervention was similar between groups or indicated reductions favoring the
HIGH group for all outcomes. These findings were consistent with the per-protocol
analysis of the HIGH group, with the exception of L-Dex and pain as upper CI’s
indicated a slight increase beyond the predetermined equivalence margin. However,
in general, care should be taken when interpreting the 39 week follow-up results as
no data regarding upper-extremity resistance exercise behavior was collected post-
intervention, and is a limitation of this study. Consequently, we cannot determine
whether effects seen at 39 weeks were a result of / or decline in resistance exercise or
other unknown factors.
Additional limitations should be considered when interpreting findings. First,
usual care in Denmark includes municipality lead rehabilitation programs and was
therefore available for all participants irrespective of group allocation. These
programs are generally offered one to two times per week and consist of breast
cancer-specific range of motion exercises, instruction in self-massage, as well as
aerobic and / or resistance exercise at low to moderate intensities. It is thus likely that
a proportion of those in the LOW group, also participated in resistance-based
exercise at low to moderate loads during the intervention period. While there exists
21
uncertainty as to the extent of this potential bias, the impact on findings would likely
dilute differences between interventions. In addition, though groups were statistically
balanced at baseline, it should be noted that more participants in the LOW group had
ALND and had been diagnosed with BCRL at baseline potentially swaying the
results in favor of the HIGH group. Further, in all 28% of the sample are missing
DXA inter-arm volume data due to body dimensions exceeding the scanning area,
why caution in generalizing these findings to obese women is required. Future
studies should be aware of this limitation and perform separate arm scans (50) as an
alternative for these individuals. Also, to strengthen BCRL data, extracellular fluid
measured by BIS was added to the test battery from participant 71 forward (54% of
the sample). Therefore, complete data was not available for these two outcomes.
Nonetheless, the comprehensive assessment of BCRL used in this study (that is, two
objective methods of assessment, alongside self-report) ensured that each participant
contributed 100% data for at least one outcome measure and adds strength to these
findings.
Strengths of the study include the randomized design as well as blinded
assessments and analyses. Further, intention-to-treat analyses were performed for all
outcomes as well as per-protocol analyses of HIGH participants with adherence rates
> 65% for BCRL outcomes, and consistency in findings was observed. In addition,
this study targeted breast cancer survivors who were physically inactive before
diagnosis. This is important as fear of lymphedema has been identified as a barrier
for physical activity and especially vigorous or strength activities (51). This, in turn
may lead to avoidance and non-adoption of regular physical activity and thereby
further increasing risk of BCRL for this significant group (1). Also, attitude towards
22
exercise can be transformed from having no priority to being highly prioritized if
support to adopt exercise is received during adjuvant chemotherapy (52). This is of
potential importance for long term exercise behavioral change, ultimately leading to
better health outcomes (53, 54). Finally, the equivalence design was considered the
most appropriate for testing our hypothesis in regard to BCRL outcomes. The value
and impact of establishing equivalence depends on how well the equivalence margin
can be justified in terms of relevant evidence and clinical judgement. Equivalence
margins ideally represent the maximum clinically acceptable difference that one is
willing to accept in return for the secondary benefits of a new therapy (36), whereas
a narrower equivalence margin makes it more difficult to establish equivalence (36).
A more conservative equivalence margin for all outcomes was purposely set in order
to ensure credibility of results. Arguably though, this may have created confidence
limits with an unnecessarily narrow interval rendering conclusions of non-
equivalence.
In conclusion, findings from this study suggest that breast cancer survivors
who are physically inactive before diagnosis benefit from and can safely participate
in a multimodal intervention that includes supervised, heavy-load resistance exercise
of the upper-extremities during adjuvant taxane-based chemotherapy. Importantly, as
this study targeted breast cancer survivors with multiple risk factors for developing
BCRL (surgery, physically inactive, overweight, taxane-based chemotherapy),
applicability extends to those considered at additional risk for developing BCRL. As
such, these findings can be used to encourage adoption of exercise including heavy-
load resistance exercise during and following breast cancer treatment.
23
Funding
This study was one of several studies conducted under The Center for Integrated
Rehabilitation of Cancer Patients (CIRE), Copenhagen, Denmark. CIRE was
established and supported by the Danish Cancer Society and the Novo Nordic
Foundation. The study also received funding from Trygfonden Denmark under Grant
number 7-12-0401.
Disclosure of interest
The authors report no conflict of interest.
Acknowledgements
We greatly thank the staff at the Department of Clinical Physiology and Nuclear
Medicine at the Copenhagen University Hospital, Rigshospitalet for collaboration in
data collection, and the participants for their dedication to the study.
24
References 1. DiSipio T, Rye S, Newman B, Hayes S. Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis. Lancet Oncol. 2013;14(6):500-15. Epub 2013/04/02. doi: 10.1016/s1470-2045(13)70076-7. PubMed PMID: 23540561. 2. Boyages J, Kalfa S, Xu Y, Koelmeyer L, Mackie H, Viveros H, et al. Worse and worse off: the impact of lymphedema on work and career after breast cancer. Springerplus. 2016;5:657. doi: 10.1186/s40064-016-2300-8. PubMed PMID: 27330922; PubMed Central PMCID: PMCPMC4870504. 3. Morgan PA, Franks PJ, Moffatt CJ. Health-related quality of life with lymphoedema: a review of the literature. Int Wound J. 2005;2(1):47-62. Epub 2006/05/26. doi: 10.1111/j.1742-4801.2005.00066.x. PubMed PMID: 16722853. 4. Fu MR, Ridner SH, Hu SH, Stewart BR, Cormier JN, Armer JM. Psychosocial impact of lymphedema: a systematic review of literature from 2004 to 2011. Psychooncology. 2013;22(7):1466-84. doi: 10.1002/pon.3201. PubMed PMID: 23044512; PubMed Central PMCID: PMCPMC4153404. 5. Mortimer PS, Rockson SG. New developments in clinical aspects of lymphatic disease. J Clin Invest. 2014;124(3):915-21. doi: 10.1172/JCI71608. PubMed PMID: 24590276; PubMed Central PMCID: PMCPMC3938261. 6. Schmidt ME, Wiskemann J, Ulrich CM, Schneeweiss A, Steindorf K. Self-reported physical activity behavior of breast cancer survivors during and after adjuvant therapy: 12 months follow-up of two randomized exercise intervention trials. Acta Oncol. 2017;56(4):618-27. Epub 2017/01/14. doi: 10.1080/0284186X.2016.1275776. PubMed PMID: 28084890. 7. Demark-Wahnefried W, Campbell KL, Hayes SC. Weight management and its role in breast cancer rehabilitation. Cancer. 2012;118(8 Suppl):2277-87. Epub 2012/04/18. doi: 10.1002/cncr.27466. PubMed PMID: 22488702; PubMed Central PMCID: PMC3812811. 8. Vagenas D, DiSipio T, Battistutta D, Demark-Wahnefried W, Rye S, Bashford J, et al. Weight and weight change following breast cancer: evidence from a prospective, population-based, breast cancer cohort study. BMC Cancer. 2015;15:28. doi: 10.1186/s12885-015-1026-2. PubMed PMID: 25637285; PubMed Central PMCID: PMCPMC4318545. 9. Markes M, Brockow T, Resch KL. Exercise for women receiving adjuvant therapy for breast cancer. Cochrane Database Syst Rev. 2006(4):CD005001. Epub 2006/10/21. doi: 10.1002/14651858.CD005001.pub2. PubMed PMID: 17054230. 10. Makari-Judson G, Judson CH, Mertens WC. Longitudinal patterns of weight gain after breast cancer diagnosis: observations beyond the first year. Breast J. 2007;13(3):258-65. Epub 2007/04/28. doi: 10.1111/j.1524-4741.2007.00419.x. PubMed PMID: 17461900. 11. Stenholm S, Harris TB, Rantanen T, Visser M, Kritchevsky SB, Ferrucci L. Sarcopenic obesity: definition, cause and consequences. Curr Opin Clin Nutr Metab Care. 2008;11(6):693-700. doi: 10.1097/MCO.0b013e328312c37d. PubMed PMID: 18827572; PubMed Central PMCID: PMCPMC2633408.
25
12. Christensen JF, Jones LW, Andersen JL, Daugaard G, Rorth M, Hojman P. Muscle dysfunction in cancer patients. Ann Oncol. 2014;25(5):947-58. doi: 10.1093/annonc/mdt551. PubMed PMID: 24401927. 13. Csapo R, Alegre LM. Effects of resistance training with moderate vs heavy loads on muscle mass and strength in the elderly: A meta-analysis. Scand J Med Sci Sports. 2016;26(9):995-1006. doi: 10.1111/sms.12536. PubMed PMID: 26302881. 14. American College of Sports Medicine position stand. Progression models in resistance training for healthy adults. Med Sci Sports Exerc. 2009;41(3):687-708. Epub 2009/02/11. doi: 10.1249/MSS.0b013e3181915670. PubMed PMID: 19204579. 15. Paramanandam VS, Roberts D. Weight training is not harmful for women with breast cancer-related lymphoedema: a systematic review. J Physiother. 2014;60(3):136-43. Epub 2014/08/05. doi: 10.1016/j.jphys.2014.07.001. PubMed PMID: 25086730. 16. Cheema BS, Kilbreath SL, Fahey PP, Delaney GP, Atlantis E. Safety and efficacy of progressive resistance training in breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat. 2014;148(2):249-68. Epub 2014/10/18. doi: 10.1007/s10549-014-3162-9. PubMed PMID: 25324019. 17. Nelson NL. Breast Cancer-Related Lymphedema and Resistance Exercise: A Systematic Review. J Strength Cond Res. 2016;30(9):2656-65. doi: 10.1519/JSC.0000000000001355. PubMed PMID: 26840439. 18. Keilani M, Hasenoehrl T, Neubauer M, Crevenna R. Resistance exercise and secondary lymphedema in breast cancer survivors-a systematic review. Support Care Cancer. 2016;24(4):1907-16. doi: 10.1007/s00520-015-3068-z. PubMed PMID: 26715294. 19. Bloomquist K, Oturai P, Steele ML, Adamsen L, Moller T, Christensen KB, et al. Heavy-Load Lifting: Acute Response in Breast Cancer Survivors at Risk for Lymphedema. Med Sci Sports Exerc. 2017. Epub 2017/10/11. doi: 10.1249/MSS.0000000000001443. PubMed PMID: 28991039. 20. Moller T, Lillelund C, Andersen C, Ejlertsen B, Norgaard L, Christensen KB, et al. At cancer diagnosis: a 'window of opportunity' for behavioural change towards physical activity. A randomised feasibility study in patients with colon and breast cancer. BMJ Open. 2013;3(11):e003556. Epub 2013/11/06. doi: 10.1136/bmjopen-2013-003556. PubMed PMID: 24189081; PubMed Central PMCID: PMC3822303. 21. Moller T, Lillelund C, Andersen C, Bloomquist K, Christensen KB, Ejlertsen B, et al. The challenge of preserving cardiorespiratory fitness in physically inactive patients with colon or breast cancer during adjuvant chemotherapy: a randomised feasibility study. BMJ Open Sport Exerc Med. 2015;1(1):e000021. doi: 10.1136/bmjsem-2015-000021. PubMed PMID: 27900123; PubMed Central PMCID: PMCPMC5117008. 22. Authority DHaM. Physical activity: recommendations for adults (18-64 years old) 2013. Available from: http://www.sst.dk/English/Health_promotion/Physical_activity/Recommendations_for_adults.aspx. 23. Adamsen L, Quist M, Andersen C, Moller T, Herrstedt J, Kronborg D, et al. Effect of a multimodal high intensity exercise intervention in cancer patients undergoing chemotherapy: randomised controlled trial. BMJ. 2009;339:b3410. Epub
26
2009/10/15. doi: 10.1136/bmj.b3410. PubMed PMID: 19826172; PubMed Central PMCID: PMC2762035. 24. Bloomquist K, Karlsmark T, Christensen KB, Adamsen L. Heavy resistance training and lymphedema: prevalence of breast cancer-related lymphedema in participants of an exercise intervention utilizing heavy load resistance training. Acta Oncol. 2014;53(2):216-25. Epub 2013/11/08. doi: 10.3109/0284186x.2013.844356. PubMed PMID: 24195690. 25. Newman AL, Rosenthall L, Towers A, Hodgson P, Shay CA, Tidhar D, et al. Determining the precision of dual energy x-ray absorptiometry and bioelectric impedance spectroscopy in the assessment of breast cancer-related lymphedema. Lymphat Res Biol. 2013;11(2):104-9. Epub 2013/06/19. doi: 10.1089/lrb.2012.0020. PubMed PMID: 23772720. 26. Brorson H, Ohlin K, Olsson G, Karlsson MK. Breast cancer-related chronic arm lymphedema is associated with excess adipose and muscle tissue. Lymphat Res Biol. 2009;7(1):3-10. Epub 2009/02/24. doi: 10.1089/lrb.2008.1022. PubMed PMID: 19231988. 27. Ward LC, Dylke E, Czerniec S, Isenring E, Kilbreath SL. Confirmation of the reference impedance ratios used for assessment of breast cancer-related lymphedema by bioelectrical impedance spectroscopy. Lymphat Res Biol. 2011;9(1):47-51. Epub 2011/03/23. doi: 10.1089/lrb.2010.0014. PubMed PMID: 21417767. 28. Cornish BH, Jacobs A, Thomas BJ, Ward LC. Optimizing electrode sites for segmental bioimpedance measurements. Physiol Meas. 1999;20(3):241-50. Epub 1999/09/04. PubMed PMID: 10475578. 29. Hayes S, Janda M, Steele M, et al. Identifying diagnostic criteria for upper- and lower-limb lymphoedema Impedimed Limited: Queensland University of Technology Faculty of Health, School of Public Health and Social Work and Institute of Health and Biomedical Innovation; 2016 [updated 3 July 2017; cited 2017 31 May]. 17]. Available from: https://eprints.qut.edu.au/view/person/Hayes,_Sandra.html#group_report. 30. Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken). 2011;63 Suppl 11:S240-52. doi: 10.1002/acr.20543. PubMed PMID: 22588748. 31. Cormie P, Galvao DA, Spry N, Newton RU. Neither heavy nor light load resistance exercise acutely exacerbates lymphedema in breast cancer survivors. Integr Cancer Ther. 2013. Epub 2013/02/27. doi: 10.1177/1534735413477194. PubMed PMID: 23439658. 32. Levinger I, Goodman C, Hare DL, Jerums G, Toia D, Selig S. The reliability of the 1RM strength test for untrained middle-aged individuals. J Sci Med Sport. 2009;12(2):310-6. doi: 10.1016/j.jsams.2007.10.007. PubMed PMID: 18078784. 33. Sprangers MA, Groenvold M, Arraras JI, Franklin J, te Velde A, Muller M, et al. The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field
27
study. J Clin Oncol. 1996;14(10):2756-68. doi: 10.1200/JCO.1996.14.10.2756. PubMed PMID: 8874337. 34. Nguyen J, Popovic M, Chow E, Cella D, Beaumont JL, Chu D, et al. EORTC QLQ-BR23 and FACT-B for the assessment of quality of life in patients with breast cancer: a literature review. J Comp Eff Res. 2015;4(2):157-66. doi: 10.2217/cer.14.76. PubMed PMID: 25825844. 35. Cohen J. Statistical power analysis for the behavioral sciences. Second ed: Academic press; 1977. 36. Walker E, Nowacki AS. Understanding equivalence and noninferiority testing. J Gen Intern Med. 2011;26(2):192-6. doi: 10.1007/s11606-010-1513-8. PubMed PMID: 20857339; PubMed Central PMCID: PMCPMC3019319. 37. Stout Gergich NL, Pfalzer LA, McGarvey C, Springer B, Gerber LH, Soballe P. Preoperative assessment enables the early diagnosis and successful treatment of lymphedema. Cancer. 2008;112(12):2809-19. doi: 10.1002/cncr.23494. PubMed PMID: 18428212. 38. Westlake WJ. Use of confidence intervals in analysis of comparative bioavailability trials. J Pharm Sci. 1972;61(8):1340-1. PubMed PMID: 5050398. 39. Cormie P, Pumpa K, Galvao DA, Turner E, Spry N, Saunders C, et al. Is it safe and efficacious for women with lymphedema secondary to breast cancer to lift heavy weights during exercise: a randomised controlled trial. J Cancer Surviv. 2013;7(3):413-24. Epub 2013/04/23. doi: 10.1007/s11764-013-0284-8. PubMed PMID: 23604998. 40. Giordano SH, Lin YL, Kuo YF, Hortobagyi GN, Goodwin JS. Decline in the use of anthracyclines for breast cancer. J Clin Oncol. 2012;30(18):2232-9. Epub 2012/05/23. doi: 10.1200/JCO.2011.40.1273. PubMed PMID: 22614988; PubMed Central PMCID: PMCPMC3397719. 41. Group DBCC. Danish Breast Cancer Coopertive Group; Retningslinjer Medicinsk Behandling 2017 [updated April 2017]. Available from: http://www.dbcg.dk/PDF%20Filer/Kap_6_Medicinsk_behandling-07.04.2017.pdf. 42. Swaroop MN, Ferguson CM, Horick NK, Skolny MN, Miller CL, Jammallo LS, et al. Impact of adjuvant taxane-based chemotherapy on development of breast cancer-related lymphedema: results from a large prospective cohort. Breast Cancer Res Treat. 2015;151(2):393-403. doi: 10.1007/s10549-015-3408-1. PubMed PMID: 25940996; PubMed Central PMCID: PMCPMC4432026. 43. Kilbreath SL, Refshauge KM, Beith JM, Ward LC, Lee M, Simpson JM, et al. Upper limb progressive resistance training and stretching exercises following surgery for early breast cancer: a randomized controlled trial. Breast Cancer Res Treat. 2012. Epub 2012/01/31. doi: 10.1007/s10549-012-1964-1. PubMed PMID: 22286332. 44. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol. 1998;16(1):139-44. Epub 1998/01/24. doi: 10.1200/JCO.1998.16.1.139. PubMed PMID: 9440735. 45. Klassen O, Schmidt ME, Ulrich CM, Schneeweiss A, Potthoff K, Steindorf K, et al. Muscle strength in breast cancer patients receiving different treatment regimes. J Cachexia Sarcopenia Muscle. 2017;8(2):305-16. doi: 10.1002/jcsm.12165. PubMed PMID: 27896952; PubMed Central PMCID: PMCPMC5377413.
28
46. Harrington S, Padua D, Battaglini C, Michener LA. Upper extremity strength and range of motion and their relationship to function in breast cancer survivors. Physiother Theory Pract. 2013;29(7):513-20. doi: 10.3109/09593985.2012.757683. PubMed PMID: 23343035. 47. Brown JC, Huedo-Medina TB, Pescatello LS, Pescatello SM, Ferrer RA, Johnson BT. Efficacy of exercise interventions in modulating cancer-related fatigue among adult cancer survivors: a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2011;20(1):123-33. doi: 10.1158/1055-9965.EPI-10-0988. PubMed PMID: 21051654. 48. Schwartz AL, Winters-Stone K, Gallucci B. Exercise effects on bone mineral density in women with breast cancer receiving adjuvant chemotherapy. Oncol Nurs Forum. 2007;34(3):627-33. Epub 2007/06/19. doi: 10.1188/07.onf.627-633. PubMed PMID: 17573321. 49. Battaglini C, Bottaro M, Dennehy C, Rae L, Shields E, Kirk D, et al. The effects of an individualized exercise intervention on body composition in breast cancer patients undergoing treatment. Sao Paulo Med J. 2007;125(1):22-8. Epub 2007/05/17. PubMed PMID: 17505681. 50. Gjorup C, Zerahn B, Hendel HW. Assessment of volume measurement of breast cancer-related lymphedema by three methods: circumference measurement, water displacement, and dual energy X-ray absorptiometry. Lymphat Res Biol. 2010;8(2):111-9. Epub 2010/06/30. doi: 10.1089/lrb.2009.0016. PubMed PMID: 20583873. 51. Sander AP, Wilson J, Izzo N, Mountford SA, Hayes KW. Factors that affect decisions about physical activity and exercise in survivors of breast cancer: a qualitative study. Phys Ther. 2012;92(4):525-36. doi: 10.2522/ptj.20110115. PubMed PMID: 22156026. 52. Adamsen L, Andersen C, Lillelund C, Bloomquist K, Moller T. Rethinking exercise identity: a qualitative study of physically inactive cancer patients' transforming process while undergoing chemotherapy. BMJ Open. 2017;7(8):e016689. Epub 2017/08/26. doi: 10.1136/bmjopen-2017-016689. PubMed PMID: 28838897; PubMed Central PMCID: PMCPMC5629696. 53. Holmes MD, Chen WY, Feskanich D, Kroenke CH, Colditz GA. Physical activity and survival after breast cancer diagnosis. JAMA. 2005;293(20):2479-86. doi: 10.1001/jama.293.20.2479. PubMed PMID: 15914748. 54. Fong DY, Ho JW, Hui BP, Lee AM, Macfarlane DJ, Leung SS, et al. Physical activity for cancer survivors: meta-analysis of randomised controlled trials. BMJ. 2012;344:e70. Epub 2012/02/02. doi: 10.1136/bmj.e70. PubMed PMID: 22294757; PubMed Central PMCID: PMCPMC3269661.
29
Captions for Figures
Figure 1. Flow of participants from recruitment and through the trial
Table 1. Overview of HIGH and LOW interventions
HIGH intervention
Monday Tuesday Wednesday Thursday Friday
Part I:’Body and Cancer’ 6 weeks, 9 h/week
Aerobic and resistance
exercise (1.5 h)
Relaxation (0.5 h)
Swedish massage (0.5 h)
Body awareness (1.5 h)
Relaxation (0.5 h)
Aerobic and resistance
exercise (2 h)
Relaxation (0.5 h)
Aerobic and resistance
exercise (1.5 h)
Relaxation (0.5 h)
Swedish massage (0.5 h)
Part II: ‘All-sport’ 6 weeks, 6 h/week
Aerobic and resistance
exercise and e.g.
ballgames, dancing (2 h)
Aerobic and resistance
exercise and e.g.
ballgames, dancing (2 h)
Aerobic and resistance
exercise and e.g. ballgames,
dancing (2 h)
LOW intervention
Week 1 Week 2 Week 4 Week 6 Week 9 Week 12
Pedometer
consultation
Pedometer
consultation
Pedometer
consultation
Pedometer
consultation
Pedometer
consultation
Pedometer
consultation
Both interventions
Baseline Week 6 Week 12 Week 39
Health promotion counselling Health promotion counselling Health promotion counselling Health promotion counselling
Characteristics Total (n = 153) HIGH (n = 75) LOW (n = 78)
Age (years), mean ± SD 51.7 ± 9.4 51.5 ± 9.6 52.0 ± 9.3
BMI (kg/m2), mean ± SD 26.1 ± 5.1 26.2 ± 5.3 26.0 ± 4.9
Cancer stage, n (%)
Stage 1
Stage 2
Stage 3
56 (36.6%)
81 (52.9%)
16 (10.5%)
31 (41.3%)
36 (48.0%)
8 (10.7%)
25 (31.1%)
45 (57.7%)
8 (10.3%)
Breast surgery, n (%)
Lumpectomy
Mastectomy
Mastectomy plus expander
90 (58.8%)
56 (36.6%)
7 (4.6%)
47 (62.7%)
26 (34.7%)
2 (2.7%)
43 (55.1%)
30 (38.5%)
5 (6.4%)
Axillary surgery, n (%)
Axillary lymph node dissection
Sentinel node biopsy
61 (39.9%)
92 (60.1%)
26 (34.7%)
49 (65.3%)
35 (44.9%)
43 (55.1%)
Nodes removed, median (IQR) 3 (2-17) 3 (1-15) 5 (2-19)
Surgery on dominant side*, n (%) 76 (49.7%) 39 (52.0%) 37 (47.4%)
No. of seroma drainages, median (IQR) 1 (0-5) 1 (0-5) 1 (0-5)
Chemotherapy, n (%)
3-wkly CE x 3 -> 3 wkly docetaxel x 3
3-wkly CE x 3 -> 1 wkly paclitaxel x 9
Other
130 (85.0%)
19 (12.4%)
4 (2.6%)
66 (86.7%)
8 (10.7%)
1 (1.3%)
64 (82.1%)
11 (14.1%)
3 (3.9%)
Observations of swelling**, n (%)
Extremity (hand, underarm, overarm)
Body (breast, torso)
Both (body & extremity)
5 (3.3%)
31 (20.5%)
11 (7.3%)
2 (2.7%)
14 (18.9%)
3 (4.1%)
3 (3.9%)
17 (22.1%)
8 (10.4%)
Treatment related to lymphedema**, n (%)
Preventatively
Existing lymphedema
4 (2.6%)
5 (3.3%)
1 (1.4%)
1 (1.4%)
3 (3.9%)
4 (5.2%)
Symptom subscales EORTC-BR23
Arm symptoms, mean ± SD
Breast symptoms, mean ± SD
16.2±19.0
18.9±16.1
15.6±20.1
18.6±16.4
16.8±18.0
19.2±16.0
L-Dexa, mean ± SD -0.3±5.1 -0.6±3.6 0.1±6.2
Table 2. Participant characteristics at baseline
Volume % differenceb, mean ± SD 1.3±19.8 0.6 ±19.7 1.9±20.0
Upper-extremity strength (RM)c, mean ± SD 29.4±8.3 29.0±8.1 29.8±8.
Not included *n = 4 missing; **n = 2 missing; a n=73 (n = 70 bioimpedance spectroscopy not available, n = 1 missing, n = 2 bilateral axillary surgery); b n =35 (n = 5 bilateral axillary surgery, n = 30 exceeded DXA scan area); c n = 15 (n = 14 post-surgery restrictions, n =1 precautionary due to arm swelling) Abbreviations BMI, body mass index; SD, standard deviation; CE, cyclophosphamide & epirubicin; pctl, percentile/IQR, interquartile range
Baseline 12 weeks 39 weeks
L-Dex > 10 a n n n
HIGH
LOW
39
41
0 (0.0%)
2 (4.9%)
33
31
3 (9.1%)
2 (6.5%)
41
34
4 (9.8%)
3 (8.8%)
Inter-arm volume % difference > 5% b
HIGH
LOW
55
63
15 (27.3%)
15 (23.8%)
45
51
14 (31.1%)
13 (25.5%)
50
49
12 (24.0%)
13 (26.5%)
Observed difference in size between sides within the last week c
HIGH
LOW
74
77
19 (25.7%)
28 (36.4%)
62
63
18 (29.0%)
13 (20.6%)
62
59
21 (33.9%)
22 (37.3%)
Based on all available data for each outcome.a Maximum n = 81 due to bilateral axillary surgery (n =2) and BIS not available (n = 70). At 39 weeks BIS was available for twelve of these particicpants and included in the analysis ; b Maximum n = 148 due to bilateral axillary surgery (n = 5), n = 30, 28, 14 exceeded DXA scan area, respectively at baseline, 12 and 39 weeks and were therefore not included in the analysis); c Of the participants that observed swelling at: baseline n = 31 (66%), 12 weeks n = 8 (25.8%), 39 weeks n = 17 (39.5%) reported swelling located to the body (breast , torso) only
Table 3. Lymphedema point prevalence. Number of participants (%)
Table 4. Equivalence between groups for BCRL outcomes
Mean difference* Equivalence 90% CI
L-Dex (±5.0)a (n =81)** n
12 weeks 64 0.4 -2.5 to 3.2
39 weeks 63 0.7 -2.2 to 3.6
Inter-arm volume % difference (±3.0)a (n =148)**
12 weeksǂ 86 -3.5 -17.3 to 10.3b
39 weeksǂ 83 -1.7 -7.7 to 4.3b
Pain (±1.0)a
(n =153)**
12 weeks 124 -0.7 -1.3 to 0b
39 weeks 121 -0.8 -1.5 to -0.1b
Heaviness (±1.0)a (n =153)**
12 weeks 124 -0.2 -0.6 to 0.2
39 weeks 121 0.0 -0.7 to 0.6
Tightness (±1.0)a
(n =153)**
12 weeks 124 -0.1 -0.8 to 0.6
39 weeks 121 -1.0 -1.8 to 0.2b
Swelling (±1.0)a
(n =153)**
12 weeks 124 0.2 -0.4 to 0.8
39 weeks 120 0.0 -0.8 to 0.7
*Mean difference between groups with HIGH as comparator (HIGH minus LOW); **Maximum n; ǂn = 38 and 30 not included at 12 and 39 weeks respectively, due to body dimension exceeding the DXA scan area; aPre-determined equivalence margin; Bold = equivalence not demonstrated; bnegative deviation reflecting reductions beyond the equivalence margin favoring the HIGH group
Variable Baseline 12 weeks 39 weeks 12 weeks - baseline 39 weeks-baseline
Mean (SD) Mean (SD) Mean (SD) n Δ (90 % CI) n Δ (90 % CI)
L-Dex (±5.0)a -0.8 (3.3) 0.9 (6.6) 1.5 (5.3) 21* 1.7 (-0.8 to 4.2) 21* 3.2 (0.9 to 5.5)c
Inter-arm volume
% difference (±3.0)a
5.3 (23.0) 4.3 (27.2) 0.6 (7.4) 21** -3.1 (-19.5 to 13.4)b 26** -5.0 (-12.8 to 2.9)b
Pain (±1.0)a 1.0 (1.7) 0.6 (1.2) 1.4 (2.5) 32 -0.4 (-0.9 to 0.1) 33 0.4 (-0.4 to 1.2)c
Heaviness (±1.0)a 0.5 (1.3) 0.3 (1.1) 0.9 (1.7) 32 -0.2 (-0.4 to 0.1) 33 0.4 (0.0 to 0.8)
Tightness (±1.0)a 1.6 (2.4) 0.8 (1.9) 0.4 (0.8) 32 -0.9 (-1.5 to -0.2)b 33 -1.2 (-2.0 to -0.5)b
Swelling (±1.0)a 1.1 (2.0) 1.0 (1.8) 1.0 (1.8) 32 -0.1 (-0.7 to 0.6) 33 -0.1 (-0.6 to 0.5)
a Pre-determined equivalence margin; *maximum n = 21; Bold = equivalence not demonstrated;**maximum n = 32; b negative deviation reflecting reductions beyond the equivalence margin; c positive deviation reflecting increases beyond the equivalence
Table 5. Per-protocol equivalence of BCRL outcomes in participants with >65% adherence to HIGH (n = 33)
Δ 6 weeks‐baseline Δ 12 weeks‐baseline Δ 39 weeks‐baseline
Variable n Mean Δ (95% CI)
Group difference (95% CI) n
Mean Δ (95% CI)
Group difference (95% CI) n
Mean Δ (95% CI)
Group difference (95% CI)
Muscular strength 1 RM (kg)* Chest press HIGH LOW
58 51
5 (3 to 6) 1 (‐1 to 2)
4 (2 to 6)
56 55
4 (3 to 6) 1 (0 to 3)
3 (1 to 5)
50 44
3 (1 to 5) 1 (‐1 to 3)
2 (0 to 5)
EORTC QLQ‐BR23 scores** Body Image HIGH LOW
62 61
2 (‐3 to 7) ‐1 (‐6 to 3)
4 (‐3 to 10)
60 62
‐3 (‐9 to 2) ‐6 (‐11 to ‐1)
2 (‐5 to 10)
61 56
7 (2 to 11)a
6 (1 to 11)a
1 (‐6 to 8)
Systemic therapy ǂ HIGH LOW
63 62
5 (1 to 10)a
4 (‐1 to 9)
1 (‐6 to 8)
61 65
7 (2 to 12)a
9 (4 to 14)a
‐2 (‐9 to 6)
61 57
‐19 (‐23 to ‐15)b
‐20 (‐24 to ‐16)c
1 (‐5 to 7)
Breast symptoms HIGH LOW
62 62
‐6 (‐9 to ‐2)a
‐7 (10 to ‐3)a
1 (‐4 to 6)
60 64
‐11 (‐15 to ‐7)b
‐9 (‐12 to ‐5)a
‐2 (‐8 to 3)
59 55
‐4 (‐9 to 1) 1 (‐4 to 6)
‐4 (‐12 to
3) Arm symptoms HIGH LOW
62 62
‐4 (‐8 to 0)a
‐5 (‐10 to ‐1)a
1 (‐5 to 7)
60 65
‐6 (‐10 to ‐1)a
‐4 (‐8 to 1)
‐2 (‐8 to 4)
59 56
‐1 (‐6 to 4) 3 (‐2 to 9)
‐4 (‐12 to
3)
Abbreviations: CI, confidence interval; Bold = statistical difference (p <0.05); *No upper-extremity strength measures on one participant (LOW) at baseline due to visible and untreated swelling. No upper-extremity strength assessment at subsequent data collections as the participant was receiving treatment for lymphedema. Three participants (2 HIGH, 1 LOW) were not assessed for upper-extremity strength at 6, 12 and 39 weeks, as a precautionary measure due to swelling or because participants refused. An additional participant (HIGH) received treatment for lymphedema at 12 and 39 weeks and was therefore not tested; **Higher functional scores (body image) indicate higher levels of functioning, lower symptom scores (systemic therapy, arm and breast symptoms) indicate a reduction in symptoms; ǂ
Perceived treatment burden; a, b, c Subjective significance of changes from baseline in terms of a “small”, b “moderate”, c “large” (Osoba, 1998)
Table 6. Changes in upper-extremity strength and breast cancer specific functional and symptom domains
6 weeks-baseline 12 weeks-baseline 39 weeks-baseline*
Variable
n
Mean
(95% CI)
Group difference
(95% CI) n
Mean
(95% CI)
Group difference
(95% CI) n
Mean
(95% CI)
Group difference
(95% CI)
Future perspective
HIGH 62 6.(-1 to 13) 5 (-5 to 15)
60 6 (-2 to 13) 8 (-2 to 19)
61 8 (0 to 16) 6 (-5 to 17)
LOW 61 0 (-6 to 7) 62 -3 (-10 to 5) 55 2 (-6 to 10)
Sexual functioning
HIGH 61 0 (-5 to 4) 1 (-5 to 8)
58 -1 (-6 to 4) 3 (-4 to 11)
58 8 (3 to 13) 2 (-5 to 10)
LOW 62 -2 (-6 to 3) 65 -5 (-10 to 0) 57 6 (1 to 11)
Sexual enjoyment
HIGH 17 -5 (-16 to 6) -4 (-20 to 11)
16 2 (-11 to 14) 13 (-3 to 29)
20 1 (-13 to 15) -4 (-23 to 14)
LOW 20 -1 (-11 to 9) 22 -12 (-22 to -1) 25 5 (-7 to 18)
Upset by hair loss
HIGH 30 -4 (-8 to 0) 1 (-5 to 7)
20 -6 (-10 to -1) -2 (-8 to 4)
*
LOW 28 -6 (-10 to -1) 21 -4 (-8 to 1)
* Upset by hair loss not obtained at 39 weeks.
Supplementary table. Changes in breast cancer specific functional and symptom domains (EORTC‐BR23)
Appendix B: Co-authorship declarations
Appendix C: Study 1-Telephone interview guide
Telefon interview/spørgeskema
Nej, har ikke lyst til at deltage Ja, telefon aftale tid og dag___________________
OPLYSNINGER OM DIG SELV
1. Alder____________
2. Hvor høje er du (cm)? __________ Hvor meget vejer du (kg)?______________
3. Hvad er din ægteskabelige status? (Sæt kun et kryds)
Samboende 1
Lever i parforhold 2
Gift 3
Single 4
Enke 5
Separeret/fraskilt 6
4. Har du et eller flere hjemmeboende børn
Nej 0
Ja, 0-6 år 1
Ja, 7-14 år 2
Ja, > 14 år 3
5. Hvilken uddannelse har du (Sæt kun et kryds)
Under uddannelse 1
Ingen uddannelse (folkeskole) 2
Gymnasial uddannelse 3
Erhvervsuddannelse 4
Kort videregående uddannelse (under 3 år) 5
Mellemlang videregående uddannelse (3-4 år) 6
Langvarig videregående uddannelse (5 år og derover) 7
6. Hvad er din aktuelle beskæftigelses situation? (Du må gerne sætte mere end et kryds)
Studerende 1
Arbejdsløs 2
Førtidspensionist 3
Efterlønsmodtager 4
Pensioneret 5
I arbejde på deltid 6
I arbejde på fuldtid 7
Sygemeldt 8
7. Hvordan vil du kategorisere dit arbejde mht. fysisk belastning? (Sæt kun et kryds)
Ikke i arbejde 0
Ikke fysisk belastende - overvejende stillesiddende 1
(fx skole, kontor, chauffør, etc.)
Moderat fysisk belastende - involverer nogen fysisk aktivitet 2
(fx går, løfter, bærer let, etc.)
Meget fysisk belastende – overvejende tungt arbejde 3
(fx bærer tungt, gartner, etc.)
BEHANDLINGSFORLØB (Sæt kun et kryds ved hver)
8. I forbindelse med din behandling blev du opereret?
Ingen operation 0 Mastektomi 1 Bryst bevarende 2 Andet 3________________________
9. Fik du fjernet lymfeknuder?
Nej 0 Ja 1, skildvagt lymfeknude biopsi Ja 2 , antal ____________
10. Hvilket kemoterapi regime modtog du?
3 x epirubicin-cyklofosfamid (CEF)/3 x Taxotere 1 6 x Taxotere 2
Andet 3________________________
11. Har du modtaget/modtager du strålebehandling?
Nej 0 Ja 1
12. Har du modtaget/ modtager du efterbehandling?
Nej 0 Ja, endokrin 1 Ja, herceptin 2 Ja, andet 3 ___________________
13. Er du højre eller venstre håndet? Blev du opereret på den side?
a, (dominant) 1 Nej, (non-dominant) 2
14. Før din udskrivelse fra hospitalet- blev du da introduceret til et øvelsesprogram for brystopereret?
Nej 0 Ja, Kirsten Tørsleffs øvelser 1 Ja 2___________________________________________
15. Udførte du øvelser for bryst opereret (bev. træning, selv massage, etc, Kirsten Tørsleff) indtil din deltagelse i Krop og Kræft?
Nej 0 Ja, 3 x ugentlig 1 Ja, daglig 2
16. I perioden inden du påbegyndte træning i Krop og Kræft, udførte du regelmæssig (1-3x ugtlg) styrketræning af armene?
Nej 0 Ja, i kommunal regi 1__________________ Ja, fysioterapi klinik 2 Ja, på egen hånd 3
SENFØLGER I HÅND OG ARM
17. I løbet af de sidste tre måneder har du observeret en forskel i størrelse mellem højre og venstre side (Sæt kryds hvor relevant)
Ingen forskel 0
Ja, Hånd 1
Ja, Underarm 2
Ja, Overarm 3
Ja, Bryst 4
18. Hvis der var en forskel, vil du mene at størrelsesforskellen i gennemsnit var (Sæt kun et kryds)
Meget lidt, du var den eneste som kunne se det 1
Synlig for dem som kender dig, men ikke overfor fremmede 2
Meget synlig 3
19. Har armen/ området, på den opereret side, i løbet af de sidste tre måneder: (Sæt kun et kryds)
a. Føltes tung Slet ikke 0 Lidt 1 Meget 2
b. Føltes stiv Slet ikke 0 Lidt 1 Meget 2
c. Føltes hævet Slet ikke 0 Lidt 1 Meget 2
d. Føltes som om den har tabt styrke Slet ikke 0 Lidt 1 Meget 2
e. Føltes snurrende Slet ikke 0 Lidt 1 Meget 2
f. Føltes smertefuld Slet ikke 0 Lidt 1 Meget 2
g. Haft spændt hud Slet ikke 0 Lidt 1 Meget 2
20. Er du blevet diagnosticeret med lymfødem? (Sæt kun et kryds)
Nej 0 Ja 1
HVIS NEJ FORTSAT TIL 25, - HVIS JA FORTSÆT
21. Af hvem blev du diagnosticeret: (Sæt kun et kryds)
Egen læge 1
Behandlende onkolog 2
Lymfødem fysioterapeut 3
Anden (angiv hvem) _______________________ 4
22. Påbegyndt du efterfølgende lymfødem behandling hos en
Ingen behandling 1
Lymfødem fysioterapeut på sygehus 2
Lymfødem fysioterapeut privat 3
Anden (angiv hvilken)________________________ 4
Er du fortsat i behandling for lymfødem Nej 0 Ja 1
Navn på behandler:_________________________________________________
23. Hvornår blev din lymfødem diagnosticeret (Sæt kun et kryds)
Inden deltagelse i krop og kræft 1
Under deltagelse i krop og kræft 2
Inden for en måned efter deltagelse i krop og kræft 3
1-3 måneder efter deltagelse i krop og kræft 4
4-6 måneder efter deltagelse i krop og kræft 5
7-12 måneder efter deltagelse i krop og kræft 6
>12 måneder efter deltagelse i krop og kræft 7
24. Har du en opfattelse af at en af at en begivenhed udløste din lymfødem (Sæt kun et kryds)
Taget på i kropsvægt 1
Udførte tungt løft 2
Sår/rift/infektion 3
Tilskadekomst 4
Ved ikke 5
Andet (angiv hvad) 6 ______________________________
FYSISK AKTIVITET (Sæt kun et kryds)
25. Hvordan vurdere du din fysiske styrke indenfor de sidste tre måneder?
Meget dårlig 1 Dårlig 2 Moderat 3 God 4 Meget god 5
26. Hvordan vurdere du din kondition indenfor de sidste tre måneder?
Meget dårlig 1 Dårlig 2 Moderat 3 God 4 Meget god 5
27. Hvordan vurdere du dit energiniveau indenfor de sidste tre måneder?
Meget lavt 1 Lavt 2 Moderat 3 Højt 4 Meget højt 5
28. Hvilket fysisk aktivitetsniveau passer bedst på dig indenfor de sidste 3 måneder?
Stillesiddende 1
(Læser, ser fjernsyn/anden stillesiddende beskæftigelse)
Gå- og/eller cykelture under 3 timer om ugen 2
Regelmæssig fysisk aktiv mindst 3 timer om ugen 3 hvilket_______________________________________
Hård fysisk træning mere end 4 timer om ugen 4 hvilket
29. Har du udført styrketræning for armene, minimum 1-3 gange om ugen siden din afslutning i krop og kræft?
Nej 0
Ja, de første tre måneder 1
Ja, det første halve år 2
Ja, det første år 3
Ja, jeg styrketræner fortsat 4
30. Hvis Ja, træner du dine arme med belastninger (kilo) svarende til
2-3 sæt af 5-8 gentagelser 1
2-3 sæt af 8-12 gentagelser 2
2-3 sæt af 12-15 gentagelser 3
Andet, (angiv hvad)_______________________ 4
31. Tak for din deltagelse. Er der noget du evt. vil tilføje?
Må jeg kontakte dig igen?
Nej 0 Ja 1
Appendix D: Study 3
BCRL information to participants
EORTC QLQ- BR23 questionnaire
Subjective BCRL outcomes structured interview
Informationomlymfødemtildeltagerei
”Etrandomiseretkontrolleretforsøgmedopsporende
interventionogfysiskaktivitetforikke‐træningsvante
patientermedbrystkræftiadjuverendekemoterapi”
Efterenoperationmedfjernelseaflymfekirtleribrystetogarmhulenerdetalmindeligt,atoverkroppen,brystet,armenog/ellerhåndenpådenopereredesidekanhavetendenstilathævedeførstemåneder,hvorefterhævelsenaftageriløbetafenugestid.Hosenmindreprocentdel(20‐30%)opstårlymfødem.Lymfødemerenkronisktilstandogkarakteriseressomenvedvarendehævelseafoverkroppen,brystet,armenog/ellerhåndenpådenopereredeside.Tilstandenkanopståiforlængelseafoperationenellerførstflereårsenere,menoftestiløbetafdeførstetoårefteroperationen.
Idagvedviikke,hvorfornogleudviklerlymfødemogandreikkegør.Selvomårsagernebagerukendte,erenrækkerisikofaktorerblevetidentificeret.Dinrisikoforatudviklelymfødemersåledesøget,hvisdu: harfåetfjernetyderligerelymfekirtlerend
skildvagt‐lymfekirtlerneiarmhulen harfåetfjernetbrystet erovervægtig
Endvidereserdetudtilat stråleterapi kemoterapi fysiskinaktivitet
ogsåøgerrisikoenforatudviklelymfødem.
Studiervedrørendefysisktræningogudviklingaflymfødemindikerer,atmotionikkeøgerrisikoenforatudviklelymfødem.Detteerogsåvoreserfaring,ogetnyligtpublicerettværsnits‐studiefinder,at6ugersdeltagelseiKropogKræftikkeerassocieretmedenøgetrisikoforatudviklelymfødem.Mendermanglerstadigvidenomspecifikketræningsformer,ogderforvilderløbendeblivespurgtindtilvelkendtesymptomerpåbegyndendelymfødemunderdindeltagelseiprojektet.Ydermere,hvisduopleversymptomersomstårpåioverénuge,ellerhvisdueritvivl,børduhenvendedigtilKiraiprojektteamet(35457362),damankanhindrelymfødemetiatudviklesigyderligerevedatmodtagerelevantbehandlingtidligtiforløbet.
Desymptomer,somduskalværeopmærksompåioverkroppen,brystet,armenog/ellerhånden,er: hævelseiløbetafdagenudennogen
nævneværdiggrund,mærkerihudenefterf.eks.ur,ring,BH‐stopperosv.
tyngde‐ogtræthedsfornemmelse urooginogletilfældesmerter spændingsfornemmelse
Viserfremtilogglæderostilatstøttedigiatblivemerefysiskaktividekommendemåneder.
MangevenligehilsnerTom,Christina,Christian,BirgitogKira
DANISH
EORTC QLQ - BR23
Patienter fortæller undertiden, at de har følgende symptomer eller problemer. Anfør venligst, i hvilket omfang De har haft disse symptomer eller problemer inden for den forløbne uge. Besvar spørgsmålene ved at sætte en ring omkring det tal, som passer bedst til Dem.
I den forløbne uge: Slet ikke Lidt En del Meget 31. Var De tør i munden? 1 2 3 4
32. Smagte mad og drikke anderledes end normalt? 1 2 3 4
33. Havde De ondt i øjnene, var øjnene irriterede eller løb de i vand? 1 2 3 4
34. Har De haft hårtab? 1 2 3 4
35. Skal kun udfyldes, hvis De har haft hårtab: Var De ked af hårtabet? 1 2 3 4
36. Følte De Dem syg eller utilpas? 1 2 3 4
37. Havde De hedeture? 1 2 3 4
38. Havde De hovedpine? 1 2 3 4
39. Har De følt Dem mindre fysisk tiltrækkende på grund af Deres sygdom eller behandling? 1 2 3 4
40. Har De følt Dem mindre kvindelig på grund af Deres sygdom eller behandling? 1 2 3 4
41. Havde De svært ved at se på Dem selv nøgen? 1 2 3 4
42. Har De været utilfreds med Deres krop? 1 2 3 4
43. Var De bekymret for, hvordan dit helbred bliver i fremtiden? 1 2 3 4
I de sidste fire uger: Slet ikke Lidt En del Meget 44. I hvilket omfang var De interesseret i sex? 1 2 3 4
45. I hvilket omfang var De seksuelt aktiv? (med eller uden samleje) 1 2 3 4
46. Besvar kun dette spørgsmål, hvis De har været seksuelt aktiv: I hvilket omfang nød De sex? 1 2 3 4 Vær venlig at fortsætte på næste side
DANISH
I den forløbne uge: Slet ikke Lidt En del Meget 47. Havde De smerter i armen eller skulderen? 1 2 3 4 48. Var armen eller hånden hævet? 1 2 3 4 49. Var det svært at løfte armen eller bevæge den til siden? 1 2 3 4 Med "brystområdet" forstås enten det operede bryst eller det område, hvorfra brystet er fjernet: I den forløbne uge: Slet ikke Lidt En del Meget 50. Har De haft smerter i "brystområdet"? 1 2 3 4 51. Var "brystområdet" hævet? 1 2 3 4 52. Var "brystområdet" ømfindtligt? 1 2 3 4 53. Har De haft hudproblemer i "brystområdet" (fx. kløe, tørhed, afskalning)? 1 2 3 4 © Copyright 1994, 1995 EORTC Study Group on Quality of Life. All rights reserved. Version 1.0
CIRE lymfødem screening Pt. ID__________________
Dato __________________
Spørges v baseline, uge 6, 12 og 39 uger. Sæt en ring omkring de svar der passer bedst.
1. Kirurgi
Højre/venstre
Lumpektomi Mastektomi Expander
2. Lymfekirtler fjernet
Skildvagt lymfekirtel
Aksil dissektion Evt. antal fjernet____________
3. BMI_______________
4. Notere om deltager er i forløb (forebyggende el behandlende) for lymfødem og i så fald hvornår.
Baseline Nej/Ja_______________
6 uger Nej/Ja_________________
12 uger Nej/Ja________________
39 uger Nej/Ja________________
5. Har du observeret en forskel i størrelse mellem den opereret og ikke opereret side i løbet af den sidste uge?
Baseline Uge 6 Uge 12 Uge 39
Nej Nej
Nej
Nej
Ja (hvor) Ja (hvor) Ja (hvor) Ja (hvor) Fingre Hånd
Fingre Hånd
Fingre Hånd
Fingre Hånd
Underarm Underarm Underarm Underarm
Overarm Overarm Overarm Overarm Bryst Torso
Bryst Torso
Bryst Torso
Bryst Torso
.
Pt. ID__________________
6. Har du bemærket en eller flere tilstande på den opereret side i løbet af den sidste uge (0=ingen, 10=værst tænkelig)
Tilstand Baseline Uge 6 Uge 12 Uge 39
Føltes tung 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Føltes hævet 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Smerter 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Spændt hud 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Evt. Bemærkninger: (F.eks bevæge indskrænkning, serom tømning, føleforstyrrelser etc.)