Cancer Investigation

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A Systematic Review of the Outcomes Used to

Assess Upper Body Lymphedema

Robyn Sierla, Elizabeth Sian Dylke & Sharon Kilbreath

To cite this article: Robyn Sierla, Elizabeth Sian Dylke & Sharon Kilbreath (2018): A Systematic
Review of the Outcomes Used to Assess Upper Body Lymphedema, Cancer Investigation, DOI:
10.1080/07357907.2018.1517362

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CANCER INVESTIGATION
https://doi.org/10.1080/07357907.2018.1517362

REVIEW

A Systematic Review of the Outcomes Used to Assess Upper

Body Lymphedema
Robyn Sierlaa,b , Elizabeth Sian Dylkec , and Sharon Kilbreathd
a
Faculty of Health Sciences, University of Sydney, Sydeny, Australia; bOccupational Therapy Department, Royal Prince Alfred Hospital,
Sydney, Australia; cDiscipline of Physiotherapy, Faculty of Health Sciences, University of Sydney, Sydney, Australia; dFaculty of Health
Sciences, University of Sydney, Sydney, Australia

ABSTRACT ARTICLE HISTORY

Purpose: To ascertain how change in upper body lymphedema is assessed and understand Received 8 August 2017
how clinically significant change is determined. Accepted 26 August 2018
Method: A systematic search of the literature resulted in 55 eligible studies for analysis.
KEYWORDS
Results: A range of assessment methods, measurement protocols, and outcomes were used
Supportive care & Symptom
in the literature. Of the 21 studies in which thresholds for change were set a priori, 20 differ- control; Outcomes Research;
ent thresholds were reported. Breast Cancers
Conclusion: How data was measured, analysed and reported was inconsistent across stud-
ies. Consensus on a core outcome set with standardised assessment protocols and report-
ing; and investigation into empirically based minimum important differences (MID)
is needed.

Introduction life measures (5,6). Objective assessments of lym-

Lymphedema is swelling secondary to an
obstruction, impairment or other deficit in the
lymphatics. Once established, lymphedema is a
chronic and potentially progressive condition.
What starts as an increase in lymphatic fluid in
the tissues can lead to localised tissue changes,
most notably an increase in adipose fat and
thickening of the dermis (1). There is, however,
significant individual variance in the rate and
extent of these soft tissue changes (2). In light of
the varying soft tissue effects, an unpredictable
time course and only moderate reliability for
patient self-assessment (3,4), accurate and
ongoing assessment of lymphedema and its
response to treatment is a key factor in
its management.
Best practice guidelines describe a range of
subjective and objective assessment tools for
measuring lymphedema and its impact (5,6).
Subjective approaches include self-report of
symptoms such as feelings of tightness and heavi-
ness, assessment of skin changes, and quality of
phedema include:
i. Measurement of volume assessed by water
displacement; measurement of size assessed by
flexible tape measure, and measurement of size
and volume using a PerometerTM (an optoelec-
tronic limb volumeter). Volume may also be
manually derived from circumferences using a
mathematical formula.
ii. Measurement of the volume of extracellular fluid
can be assessed by bioimpedance spectroscopy
(BIS) or Tissue Dielectric Constant (TDC).
iii. Measurement of changes in tissue resistance
assessed by tonometry, a pitting test and
by palpation.
Previous attempts at meta-analyses of
lymphoedema treatment research cite heterogen-
eity of the outcome measures used as a barrier to
combining data. (7–9) As it is unclear whether
the heterogeneity arises from the variety of
assessment tools being used, the way the
outcomes are analysed or differences in the way

CONTACT Robyn Sierla rsie8518@uni.sydney.edu.au University of Sydney, Faculty of Health Sciences, PO Box 170, Lidcombe, Sydeny, 1825
Australia; Royal Prince Alfred Hospital, Occupational Therapy Department, Level 4 QE2 Building, 59 Missenden Rd, Camperdown, Sydney, 2050 Australia.
ß 2018 Taylor & Francis Group, LLC
2 R. SIERLA ET AL.
results are reported, it has not been possible to
establish a core set of outcomes to be used
in future lymphedema treatment research.
Furthermore, what a minimum important
difference (MID), or a clinically significant
change in response to a treatment or progression
of swelling for established lymphedema is
unclear. (10,11)
The primary aim of this systematic review is to
describe what measurement tools and assessment
methods are commonly used to assess change in
lymphedema presentation, and how outcomes
from the assessments are reported. The secondary
aims were to explore whether a threshold for
change was pre-determined (a priori); what
thresholds were selected, and whether there was
justification for selecting this threshold.
Methods
Literature search
Relevant studies were identified through searches
conducted in Medline, Embase, Pubmed, Web of
Science, Cinahl and Cochrane library (Appendix
1). Primary search terms used were ‘swelling/
oedema and lymphedema’ and ‘upper limb’. The
search, limited to English language sources from
2000 to March 2016 identified an initial 9971
articles. Three authors (SK, ED and RS) screened
6644 titles each (including abstracts where neces-
sary) to ensure each study was screened twice for
potential eligibility.
Studies were included in the full paper review
if they met the following inclusion criteria:

Randomised or quasi-randomised control trials,
prospective cohort studies over time, pre-post
studies; or retrospective cohort studies
over time.

Diagnosis of upper limb lymphedema with
measurable criteria set to establish the presence
of lymphedema.

Report a change over time or change with
intervention.
One hundred and seventy-one full texts were
reviewed by two authors (SK and RS) and any
disagreement was reviewed by a third author
(ED). Fifty-five studies from 19 different nations
met the inclusion criteria (Figure 1).
Data analysis
A data extraction form was developed in
MicrosoftV Access 2013 to organise the relevant
R
findings prior to undertaking the review. Data
extracted included the assessment tools used to
assess lymphedema status, as well as how
progression or response to treatment were
reported. For outcomes related to size, a hier-
archical approach to analysis was used in which
reported data were initially separated into change
in i) volume or ii) circumferential measurements.
These outcomes were then separated into further
domains of absolute or relative change and lastly
point differences, summed differences, unilateral
comparisons, or percentage difference over time.
The frequency of each outcome was tabulated. In
addition, each study was reviewed to see whether
a threshold for clinically relevant change was
stated either explicitly within the body of the text
or within the power calculation for continuous
data. In cases where the proposed thresholds
referenced another publication, the original paper
was examined to investigate whether a rationale
was described for the threshold selected.
Results
Assessment tools and measurement methods
Within and across the studies reviewed, a range
of measurement methods and assessment tools
were used to quantify change in upper body lym-
phedema (Table 1). Change in limb size was
reported for 53 of the 55 studies reviewed (Figure
2). Circumference measurements from a flexible
tape measure were the most frequently employed
approach and were used in 33 (60%) of the stud-
ies reviewed (11–43). However, methods for
measurements using a tape varied widely. For
example, intervals for circumference measure-
ments included 3 cm, 4 cm, 5 cm or 10 cm, with
starting points of either the ulnar styloid or olec-
ranon. Furthermore, only 10 of the 33 studies
using circumferences reported the position the
subject was in when measures were taken. When
reported, the positions for measurement varied,

Figure 1. PRISMA flow chart.
including i) seated with the participant’s arm
abducted to 90 degrees and resting on a measure-
ment board (26) or table (7, 15, 16); ii) partici-
pant supine, arms by their side relaxed with
elbows straight (12,20,40); iii) participant seated,
arm abducted to 30 degrees; (21) and iv) partici-
pant seated, elbow extended with the hand on
the ipsilateral knee (19).
Other tools were used to assess change in limb
size including PerometryTM in 7 (13%) studies
(10,44–49), water displacement in 20 (36%)
studies (7,11,18,22,23,28,33,39,40,50–60), and
dual-energy x-ray absorptiometry (DXA) in two
studies (4%) (15,16). Two methods of water
displacement were used to assess volume. The
standard water displacement technique measures
the volume of water displaced out of the
container when the arm is submerged
(11,18,22,23,28,33,39,40,50,52–55,57,58,60–62).
The alternate method is called inverse water volu-
metry, or shortness of water, and is where a
volume calculation is made based on the change
in the water level (7,51). Protocols for the water
displacement method were not described in all
papers reviewed. However in the papers where it
was described, it was evident that there was
inconsistency in volumes provided due to differ-
ing protocols of limb submersion depth.
CANCER INVESTIGATION 3
Submersion depth descriptions included: 45 cm
(40) above ulnar styloid, 50 cm (61), or ‘as close
to the axilla as possible’ (47). Volume measure-
ments from water displacement methods pro-
vided upper limb volume results inclusive of the
hand in all but one study (40), while volumes
derived from circumference or PerometryTM pre-
sented results did not.
Other assessment tools were used as part of a
lymphedema assessment. Bioimpedance spec-
troscopy (BIS) was used to quantify the volume
of extracellular fluid of the whole arm in 11
(22%) studies (16,24,26,33,34,44,48,57,61,63,64),
with one study also measuring the interlimb
ratio for extracellular fluid within 10 cm seg-
ments along the arm (48). The ImpedimedV
R
SFB7 was used in five studies reporting the
interlimb extracellular fluid ratio
(24,34,48,57,61) and the Impedimed U400 was
used in three studies. Other devices used for
assessing extracellular fluid volume with BIS
were the InBody S10 (64), and 3.0 Body
Composition Analyser (33,44), (BioSpace, Seoul,
Korea). Tissue Dielectric Constant
(MoistureMeterTM) was used in two studies to
measure cutaneous lymphoedema (19,47).
TonometryTM was used bilaterally in two studies
to measure tissue resistance (44,60). Dermal
4 R. SIERLA ET AL.

Table 1. Outcomes reported

Size/Volume measures Measurements taken (References) Reporting difference (References)
Circumference from a tape Intervals from ulnar styloid: Unilateral (affected side only) (20,38)
measure (n ¼ 33) 3 cm (12,33,38,40) Bilateral
4 cm (15,22,23,25,27,30,32) Single point circumference difference (14,16,28,39)
5 cm (13,26,29,35)
Difference graded (<3 cm mild; 3–5 cm mod-
10 cm (24,36,41) erate; >5 cm severe) (39)
Summed circumference difference (12,15,16,42)
Circumference difference change over time:

summed circumference (12,14,37,42)

percentage (14,22,26)
Conversion to volume (11,13,17,19,21–25,27,
29–32,35,36,38,40,41,43)
Volume - pre/post or time series
(17,19,24,25,30,32,36,43) (distal vs proximal arm
value) (38)
Volume difference - pre/post or time series
(17,19,25,29,31,35,43)
Volume difference change over time

volume (17,21,25,35,43)

percentage (13,17,21,24,25,27,29,31,32,43)
Percentage difference - pre/post or time series
(11,17,19,21,25,30,31,41,43)
Ratio – pre/post or time series (13)
Ratio change (13,21)
Water displacement Water Displacement Unilateral (affected side only) (51,54)
(n ¼ 20) (11,18,22,23,28,33,39,40,51–55,57–59,61,62) Volume - pre/post or time series
Inverse water volumetry (7,44) (7,22,53,54,57–59,61)
Volume change (22,51,54)
Bilateral
Volume - pre/post or time series (59,61)
Volume difference - pre/post or time series
(7,18,28,33,40,44,53,57–59,61)
Volume difference change over time

volume (39,40,44,60)

percentage (18,40,44,53,55,60,62)
Percentage difference - pre/post or time series
(7,11,18,35,40,57–59,61,62)
Perometer (n ¼ 7) Unilateral (affected side only)
Volume change (44)
Bilateral
Volume (10,44,48,57)
Percentage difference – pre/post or time series
(10,45,46,49,57)
Volume difference change over time

percentage (45,46)
DXA (n ¼ 2) Unilateral (affected side only)
Volume change (15,16)
Bilateral
Volume difference - pre/post or time series (15,16)
Component of Physical change
Bioimpedance Spectroscopy (n ¼ 11) Ratio (24,33,34,44,48,57,61,64) Absolute score - pre/post or time series
- segmental (48) (15,16,24,26,33,34,44,48,57,61,64)
L-Dex (15,16,26) Absolute change in score over time (44)
Other Calliper creep (35)
Dermal thickness – ultrasound (28,35)
Quantitative lymphoscintigraphy (45)
Tonometry (44,60)
Cellulitis incidence (21)
Tissue dielectric constant (19,57)
Subjective assessment
Clinician reported outcomes Palpation Pitting oedema (45,46)
Observed physical changes Physician review of clinical photos (45,46)
ISL grading scale (0–4) (39)
Campisi grading scale (1a–5) (7,51)

Patient reported outcomes Symptom report LSIDS - A (24)

Perceived size change (45) LYMQOL (10)
VAS for symptom scores
(13,15,22,26,28,32,35,37,42–44,51,55,61,65)
ISL: International Society of Lymphology; LSIDS-A: Lymphedema Symptom Intensity and Distress Scale–Arm; LYMQOL: lymphoedema quality of life ques-
tionnaire; VAS: visual analogue scale.
 CANCER INVESTIGATION 5

Water
Circumference (n=33) Perometer™ (n=20) DXA (n=2)
Displacement (n=7)

Data represenng size

Circumference (cm) Volume derived from Volume (ml)

(n=33) circumference (n=20) (n=47)

Unilateral Bilateral Unilateral Bilateral

Pre/post Reducon Pre/post Reducon Pre/post Reducon Pre/Post Reducon

Absolute (cm) Absolute (cm) Relave (%) Absolute (cm) Absolute (ml) Absolute (ml) Absolute (ml) Absolute (ml)
-single point (n=2) -summed (n=4) -single interlimb -single interlimb (n=25) (n=14) (n=22) (n=14)
-summed (n=7) difference (n=1) difference (n=1) Relave (%) Relave Relave
-summed interlimb -summed interlimb (n=5) -% (n=23) -% (n=23)
difference (n=2) difference (n=2) -rao (n=2) -rao (n=3)
Relave (%)
-summed (n=1)

Figure 2. Capturing data related to limb size

thickness was measured bilaterally by ultrasound
in two studies (28,35) One study took ultra-
sound measures of the affected limb only, while
the second measured interlimb differences.
Caliper creep using the Harpenden skinfold cal-
liper and the line method in one study meas-
ured skin thickness in the affected limb (35).
Protocols differed for the points of measure-
ment for all studies where Tissue Dielectric
Constant, Tonometry, calliper measurements
and ultrasound were used.
Participants’ self-assessment of the impact of
treatment was reported in 28 of the papers
reviewed (51%). Several used both a quality of
life (QOL) tool and a symptom report tool
(35,44–46,65). The lymphedema-specific tools
used to assess the impact of living with lymphe-
dema included the Lymphedema Symptom
Intensity and Distress Survey – Arm (LSIDS-A)
(24), and Lymphedema Quality of Life Tool
(LYMQOL) (10). Visual analogue or numerical
scales to estimate symptom severity for items
such as heaviness and tightness and pain were
used in 15 studies (13,15,22,26,28,32,35,37,42–44,
51,55,61,65). One study reported the patient’s
self-assessment of arm swelling and tissue indur-
ation (pitting) (45).
While most clinician-reported outcomes were
from objective assessment tools, subjective assess-
ments using observation or palpation were
reported in five studies. Visible changes over the
chest wall were observed from clinical photog-
raphy in one study (45). Palpated changes were
also reported, for example, using a graded assess-
ment of pitting (45,46). The International Society
of Lymphology (ISL) grading scale for lymphe-
dema (39,51), and a grading scale proposed by
Campisi (7) provided a rating of the severity of
lymphedema based on a combination of observed
and palpated changes. Measurement of the breast,
chest wall or upper quadrant of the trunk were
addressed in only two studies reviewed (24,45),
and hand lymphedema was not individually
assessed in any of the studies.
Outcome analysis and reporting
For each assessment tool and measurement
method, there was significant variance in how the
outcomes were analysed and reported (Figure 2).
Fifty-three studies reported change in volume or
size from baseline to follow up. In four studies,
only change in the measurements of the affected
limb were reported (20,38,50,54), while the
6 R. SIERLA ET AL.
remainder of the studies (n ¼ 49) reported change
in the interlimb differences from bilateral meas-
ures, often in addition to single limb calculations.
Changes in outcomes were reported in absolute
(cm and ml) and relative terms (percentage
and ratio).
Absolute changes in outcomes were reported
either pre- and post-intervention, or as a change
over time (n ¼ 41). Pre and post intervention
results were quantified using: a single limb cir-
cumference or an interlimb circumference differ-
ence at a single location (14,16,28,39); single limb
or interlimb summed circumference difference
(14,37,42); single-arm volume or inter-limb vol-
ume difference (7,10,17–19,22,24,25,28–33,35,36,
38,40,43,44,47,48,50,51,53,54,57–59,61).
outcomes were reported as a change over time
they were quantified by: reduction in a single
limb or interlimb summed circumference
difference (12,14,37,42) and reduction in a
single limb or interlimb volume difference
(15–17,21,25,35,39,40,43,44,51,60). The difference
in volume between the affected and contralateral
limb was variously labelled ‘volume excess or VE’
(43), ‘absolute oedema volume’ or ‘absolute dif-
ference’ (13), ‘excess volume or EV’ (32), or
‘oedema volume’ (51).
Relative changes in outcomes were reported
by percentage or as a ratio (n ¼ 36). These
data were reported pre and post-intervention
with the interlimb difference represented
limb  unaffected limb
by percentage ðaffected unaffected limb 100Þ (7,10,
11,17–19,25,30,31,35,40,41,43,45–47,49,51,57–59,
61,62); or ratio (13,48); or as a change
(percentage reduction) over
volume difference time 2 – interlimb volume difference time 1
ðinterlimb interlimb volume difference time 1
(7,10,17–19,25,31,35,41,43,45,46,49,51,59,62). An
interlimb ratio was derived from summed cir-
cumferences (13,21); and a percentage was
derived from (i) summed circumferences; (11)
(ii) largest circumference difference (11) or (iii)
volume difference (7,10,11,14,17–19,25,30,31,35,
40,41,43,45–47,49,51,57–59,61,62). Of the studies
reporting change in size or volume (n ¼ 53),
results were presented pre- and post-intervention
only in 15 studies (28%), by change over time in
two studies (4%), and by both in 36 studies
(68%) (Table 1).
Circumference measurements were converted
to a volume (ml) using a mathematical equation
in 20 (61%) studies (11,13,17–19,21–25,27,29–32,
35,36,38,40,41,43). (Appendix 1). Inconsistencies
were identified in the formulae used to convert
circumference data into volume. For example, the
different formulae used to calculate volume were
included: i) truncated cone (a.k.a. frustum
method) (19,23,29,36,38), which was the most
commonly used formula; ii) cylinder (a.k.a.
Kuhnke formula) (22,31,32); iii) simplified
Frustum formula; (21,30) iv) numerical integra-
tion by piecewise quadratic approximation (a.k.a.
Simpson’s rule of integration for volume) (13)
and v) one other unlabelled formula for volume
Where (24,40) (Appendix 2).
BIS was used in 11 studies (15,16,24,26,33,34,
44,48,57,61,64) of which all but one reported
change in size (64). For measurements using BIS,
the interlimb extracellular fluid volume was pre-
sented as a ratio in five studies (24,34,48,57,61)
and converted to an L-DexV score in three
R
(15,16,26) Of the remaining three studies, one
reported results by ‘arbitrary bioimpedance
machine units’ (44), one cited results in an
unpublished table (64), and the third presented
results, however, it was unclear what data were
representing (33). As no reference was made to
either interlimb differences or interlimb ratios, it
is assumed these three studies were reporting sin-
gle-limb results. Single-limb results were also
reported for ultrasound (35) and calliper (35)
measures of dermal thickness, while Tonometry
(44,60), Tissue dielectric constant (19,47), and in
one instance, ultrasound (28), were presented as
time
an interlimb difference.
100Þ:
Thresholds for change
Expected or required thresholds for change due to
treatment given were explicitly established a priori
in nine studies (14,17,21,29,44,45,48,57,59). In 10
studies (13,15,16,20,23,25,26,31,45,51), the thresh-
old for change was reported within power calcula-
tions, with two established post-priori (10,27).
Notably, the required thresholds for change were
not consistent (Table 2). Of the 21 studies in
which thresholds for change were set a priori, 20
different thresholds were reported. For randomised

Table 2. Criteria reported to signify a significant change.
Intervention
Ahmed Omar 2011 (12) LLLT (n ¼ 25)
Andersen 2000 (13) Standard treatment (compres-
sion sleeve, education,
exercise) plus manual lymph
drainage (MLD) (n ¼ 20)
Bergmann 2014 (43) Bandaging, exercise, plus
MLD (n ¼ 28)
Bordin 2009 (50) Electromechanical device –
passive exercise and
stretches (n ¼ 25)
Carati 2003 (44) LLLT (two treatment
cycles) (n ¼ 33)
Cassileth 2013 (14) Acupuncture (n ¼ 33)
Cormie 2013 (15) High load resistance
exercise (n ¼ 17)
Cormie 2013 (16) High load resistance exercise
(n ¼ 22); Low load resistance
exercise (n ¼ 21)
Damstra 2009 (51) Low pressure bandaging
20-30 mmHg (n ¼ 18)
Damstra 2009 (7) Lympho-venous anasto-
mosis (n ¼ 11)
Dayes 2013 (17) Decongestive Lymphatic
Treatment (DLT) MLD,
bandaging treatment cycle
with compression garment
on completion (n ¼ 56)
De Godoy 2015 (52) Compression garment
(novel) (n ¼ 66)
De Godoy 2013 (53) DLT (n ¼ 66)
Didem 2005 (18) DLT including MLD,
bandaging, elevation
and exercises (n ¼ 27)
Fife 2012 (19) Advanced intermittent
pneumatic compression
(IPC) device (n ¼ 18)
Fong 2014 (20) Qigong (n ¼ 11)
Forner-Cordero 2010 (32) DLT (n ¼ 171)
Godoy 2012 (54) Active exercise – pulley
system with sleeve (n ¼ 20)
Gothard 2004 (45) Vitamin E and
Pentoxyfylline (n ¼ 35)
Gothard 2004 (46) Hyperbaric oxygen
therapy (n ¼ 21)
Control
Sham LLLT (n ¼ 25)
Standard treatment
(compression sleeve,
education, exercise)
no MLD (n ¼ 22)
Bandaging, exercise,
no MLD (n ¼ 29)
LLLT (sham cycle then one
treatment cycle) (n ¼ 28)
Low load resistance exercise
(crossover design with
washout period)
Control (n ¼ 19)
High pressure bandaging
44-58 mmHg (n ¼ 18)
Compression garment
(n ¼ 39)
DLT including bandaging,
elevation and exer-
cises (n ¼ 26)
Standard IPC (n ¼ 18)
Control (n ¼ 12)
Active exercise – pulley
system without
sleeve (crossover)
Placebo (n ¼ 33)
CANCER INVESTIGATION 7
Study powered for change Threshold set a priori
Designed to detect a 20%
L/E volume# over 3 m with
p  0.05 Power ¼0.90.
Sample size of 42 required
200 ml # in L/E volume
if 3/27 achieve 30% # in
comparative arm
circumference
a level of 0.05 (5% change)
for a final sample of
17. Power ¼ 80%
Significance acknowledged as
5% (from Schmitz study) but
set to detect 2% for power
calculation of 80% for sam-
ple size of 62.
To achieve a power of 80%
with 95% reliability a sam-
ple of 741 for 10%# or 119
for a 20% # in volume.
40% # in L/E volume in a
garment over 6 weeks. 20%
# reduction in L/E volume
with DLT over and above
that achieved in garment
A medium to large effect size
of 0.7 expected, therefore a
total sample of 19 partici-
pants were required for
80% power with a ¼ 0.05
5% treatment effect difference
100 patients randomised was
calculated to allow detec-
tion of a 0.66 standardised
difference in volume b/w
the two groups assuming a
mean and SD of % # in vol-
ume of approximately 10
and 15% respectively.
(Power ¼90%, a ¼ 5%)
20% # in arm volume at
12 m “considered a clinic-
ally worthwhile
improvement.” # of two
stages for stages of pitting
(e.g. stage 3 to stage 1)
(continued)
8 R. SIERLA ET AL.
Table 2. Continued.
Intervention
Gradalski 2015 (21) DLT - with MLD
(Vodder) (n ¼ 25)
Gurdal 2012 (36) DLT (n ¼ 15)
Haghighat 2010 (55) Modified DLT þ IPC (n ¼ 56)
Jeffs 2013 (10) Self-care (with compression
garment) þ home
exercises (n ¼ 11)
Johansson 2013 (57) Weightlifting programme 3/7
– 8 weeks (n ¼ 23)
Johansson 2014 (47) Twice daily sessions of
water based exercise –
8 weeks (n ¼ 15)
Johansson 2005 (61) Low resistance exercises with Low resistance exercises
compression sleeve (n ¼ 31)
Jonsson 2009 (58) Pole walking – single
episode (n ¼ 26)
Jonsson 2014 (59) Pole walking – 3–5/7 for
8 weeks (n ¼ 23)
Kaviani 2006 (37) LLLT (n ¼ 4)
Kim 2010 (38) Active resistance
exercise þ DLT (n ¼ 20)
King 2012 (22) DLT with garment
(n ¼ 10)
Kozanoglu 2009 (42) Intermittent pneumatic
compression (IPC)
(n ¼ 24)
Letellier 2014 (11) Home exercise programme
plus water based exercise
programme (n ¼ 13)
Liao 2004 (41) DLT (n ¼ 18)
Libanore 2011 (64) Electromechanical device –
passive exercise (n ¼ 21)
Maher 2012 (48) Single session MLD with
lymphoedema (n ¼ 15)
McKenzie 2003 (40) Exercise programme (n ¼ 7)
McNeely 2004 (23) Compression bandaging
with MLD (n ¼ 25)
Mondry 2004 (39) DLT (n ¼ 20)
Ridner (24) IPC– arm (n ¼ 21)
Shaw 2007 (25) Weight reduction
programme (n ¼ 11)
Control
Compression bandag-
ing (n ¼ 26)
IPC þ SLD (n ¼ 15)
DLT (n ¼ 56)
Self-care (with compression
garment) (n ¼ 12)
Control (n ¼ 14)
without compression sleeve
(cross-over)
LLLT sham (n ¼ 4)
DLT (n ¼ 20)
DLT with bandaging
(n ¼ 11)
LLLT (n ¼ 23)
Home exercise pro-
gramme (n ¼ 12)
Single session MLD no
lymphoedema (n ¼ 15)
Control (n ¼ 7)
Compression bandaging
no MLD (n ¼ 25)
IPC– arm and trunk
(n ¼ 21)
Control (n ¼ 10)
Study powered for change Threshold set a priori
200ml - primary end point
below which the two
treatments used would be
considered as equivalent
Post-priori. For a robust
study to detect 5%# in
L/E volume. Power ¼80%,
p  0.05. Sample size to
achieve this ¼100 in
each group.
5% between group difference
considered clinically
significant
9% # in L/E volume consid-
ered clinically important;
3% #L/E volume consid-
ered clinically meaningful
according to clin-
ical experience
10%# in BIS ratio(63)
164 ml# in limb volume (69)
Sample size needed 42
(21 per group) to detect a
difference of 20% in the#
LO between the 2 groups
a ¼ 0.05 and a power
¼ 80%. Effect size calculated
from clinical results and
review of the literature with
an estimated reduction of
45% for Tx group, 25%
for control
Intention to recruit 50 based
on assumptions that dietary
intervention would benefit
50% and that 10% of con-
trol group could benefit.
Desired sample size deter-
mined using the Medical
Research Council sample
size calculation programme.
A 2-sided test Power
¼ 90%, p  0.05.
(continued)
 CANCER INVESTIGATION 9

Table 2. Continued.
Intervention
Shaw 2007 (31) Weight reduction programme
through reduced energy
intake (n ¼ 19) vs Weight
reduction programme -
low fat (n ¼ 17)
Singh 2015 (26) Moderate load resistance
exercise with compres-
sion (n ¼ 25)
Sitzia 2002 (27) MLD (n ¼ 15)
Smith 2014 (34) Acupuncture (n ¼ 10)
Smykla 2013 (49) Kinesiotape (n ¼ 20) vs Quasi-
kinesiotape (n ¼ 22)
Szuba 2002 (60) DLT with IPC (n ¼ 12)
Tsai 2009 (33) DLT with bandage (n ¼ 21)
Uzkeser 2013 (65) DLT with IPC (n ¼ 12)
Uzkeser 2015 (28) DLT with IPC (n ¼ 16)
Vignes 2013 (29) DLT – volume reduction at
4 d vs 11 d in treat-
ment (n ¼ 129)
Wilburn 2006 (30) IPC and garment (n ¼ 10)
Williams 2002 (35) MLD and garment (n ¼ 31)
Wozniewski 2001 (62) DLT (n ¼ 188)
DLT: decongestive lymphatic treatment; IPC: intermittent pneumatic compression; MLD: manual lymphatic drainage; L/E: lymphedema; SLD: self lymphatic
drainage; LLLT: low level laser therapy.
Control
Control (n ¼ 15)
Moderate load resistance
exercise without
compression (crossover)
Simplified lymphatic
drainage (n ¼ 13)
Control (n ¼ 10)
DLT (n ¼ 23)
DLT (n ¼ 11)
DLT with kinesiotape
(n ¼ 20)
DLT (n ¼ 13)
DLT with MLD (n ¼ 15)
SLD self-massage and
garment (cross-over)
SLD self-massage and
garment (cross-over)
Study powered for change Threshold set a priori
Sample size determined with
intention to recruit 60–20 in
each group based on
assumptions that dietary
intervention would benefit
50% and that 5% of control
group could benefit. It was
calculated that this sample
size would have a 90%
power to detect difference
at a 0.05 significance level
using a 2-sided test.
Sample size calculations - to
detect a change of 10 units
for L-Dex, Power ¼ 80%
and significance at 5%, 2-
tailed, 22 partici-
pants required.
Post-priori: % change in
lymphoedema volume 12%
greater with MLD over SLD.
95% confidence interval for
this suggests a true mean
difference between –3.8%
and þ27.5%. To achieve a
result with a significance
level of 0.05, Power ¼ 0.90,
56 participants would be
needed in each group.
A L/E-volume # after 4 d
>75% of the total obtained
after 11 d was considered
clinically relevant to con-
sider shortening
DLT duration

controlled trials, the thresholds for change varied
among 5%, (16) 20%, (45) or 200 m (44) volume
change or a 10 L-Dex unit change using BIS (26).
Contrastingly in parallel intervention studies, the
most common threshold set for expected change
was 5% change in volume or between-group differ-
ence (10,15,16,47). For those studies which used a
parallel or cross-over design, the threshold related
to the additional benefit obtained from one inter-
vention over another. For example, Wilburn (30)
stated a priori that the duration of treatment was
clinically relevant if the decrease in lymphedema
volume was >75% of the total decrease in volume
obtained after 11 d of treatment. Only three studies
cited other work as informing their selection of
clinically relevant change: a 5% (15), or 200 ml vol-
ume change (21), and a 10-point change in BIS
ratio or 164 ml volume change (48).
Discussion
Across the research, secondary upper limb
lymphoedema is assessed by a range of tools and
outcome measures. While outcomes included
interlimb fluid differences, dermal thickness and
patient symptom report, most studies have used
10 R. SIERLA ET AL.
Figure 3. Dimensions of physical assessment
changes in the size of the limb to evaluate treat-
ment effect. The multitude of methods under-
taken to measure, analyse and report the various
values reveal no clear picture of what method
should be used, or more importantly, the
minimally important difference. The absence of
agreed-upon thresholds for change and the
inconsistencies observed impede the evaluation
of lymphedema treatments, with several
meta-analyses citing heterogeneity of results
limiting opportunities for data summation (7–9).
Furthermore, due to the progressive nature of
lymphedema, simply looking at limb size is not
sufficient to assess the impact of a treatment; its
assessment requires a heterogeneous group of
outcome measures to appropriately capture its
multidimensional nature (66). Currently, the
combination of outcomes required to capture
meaningful change in a lymphedematous limb is
unclear. This review highlights where agreement
is needed including i) the methodology for limb
size assessment; ii) inclusion of other tools to
assess specific dimensions of lymphedema; iii)
upper body regions that require reporting and,
iv) minimally important difference.
Both within and across studies, a range of
measurement tools and reporting methods were
used to capture the same outcome, size, with
both absolute and relative changes derived from
the same data being reported in multiple ways
(13,17,19,25). There were inconsistencies in how
size data are captured and analysed. Variance was
introduced by differences in participant position-
ing, intervals and locations of circumference
measurement, as well as differing formulas used
for converting circumference to volume, and dif-
ferences in terminology used for reporting the
outcomes. Although outcomes are most
commonly reported as volume, these were often
converted from raw circumference data (cm) to
volume (ml) before being expressed as interlimb
difference as a percentage (%). In this example,
the conversion to volume is an unnecessary
double handling of data reducing the specificity
of the final outcome reported. The primary issue
for data synthesis among studies, however, is the
absence of one consistent outcome that can be
compared across studies. As such, the authors
recommend for that, as a minimum, one size-
based interlimb outcome measure expressed in
relative terms be included in all future research
(5,67). The use of a relative outcome enables
combining of data, regardless of the assessment
tool or measurement method used.
The reliance on changes in size only may
under-estimate the impact of treatment or miss
fundamental changes resulting from treatments.
Agreement was not evident for what outcome
measures were necessary to ensure all relevant
changes are captured. Clinical tools are available
to capture many dimensions of change (Figure
3), while these tools were used in some papers
the rationale for when and why they were
included was not elucidated. Bioimpedance

spectroscopy reliably measures the volume of
extracellular fluid of which lymph is a major
component (4,68). Ultrasound and calliper meas-
ures assess dermal thickening, and palpation or
TonometerTM assess tissue resistance.
Understanding which treatments impact on der-
mal thickness or tissue resistance, for example,
may assist in the prescription of more targeted
treatment approaches. To assess the impact of
this condition patient-reported outcomes related
to symptoms, function and psychosocial well-
being are also necessary (69) but were reported
in only half of the studies reviewed. Patient-
reported outcomes are gaining recognition for
their importance in health-related research (70),
particularly for chronic disease management (71).
The patient-reported outcomes observed were
primarily focussed on the assessment of symp-
toms such as discomfort, using a visual assess-
ment scale. Validated and reliable questionnaires
are available that can be used for self-report
which extend beyond symptom report to the
effects on lymphoedema on quality of life and
function, including the LSIDS-A (72) and
LYMQOL (10) found in this review. Agreement
on the use of one of these or a similar standar-
dised measure for PROs would also improve
consistency in reporting.
Outcome reporting for upper body lymphe-
dema secondary to breast cancer has been con-
fined to the arm from the wrist to axilla.
Although the search terms for this systematic
review included the terms ‘upper extremity’ and
‘upper limb’, hand lymphedema was not reported
in any of the included papers. There has been a
paucity of instruments available to objectively
measure size change in the hand (73), although
recent investigations have demonstrated that BIS
can be reliably used for assessment of hand
lymphedema (74) and techniques for hand
volume and circumference measurement have
been reported (75,76).
There has been little to no attention paid to
clinically significant change in established lym-
phedema for any outcome measure. Only one
study reviewed fluctuation of lymphedema over
different periods of time to determine the stand-
ard error of measurement to inform ‘real change’
from that of normal fluctuation (4). In the
CANCER INVESTIGATION 11
current review, we looked at whether a threshold
for change was set a priori in the studies
reviewed. All thresholds established a priori were
objective measures of size or BIS, and primarily
reduction in size (Table 2). There was no consist-
ency evident among the thresholds set a priori
with percentage reductions ranging from 2% (16)
to 60% (17). Only one study used a statistically
derived threshold based on the fluctuation of
lymphedema over time (48). While a few studies
have considered statistical significance, thresholds
for change that are clinically significant, that is,
minimum important difference (MID), are yet to
be determined or discussed. Future papers would
benefit from selecting a threshold to represent
the MID along with a rationale for why this
threshold was selected. It is currently unknown
what amount of change is needed to make a
significant impact for the patient, and whether in
fact size reduction is the primary goal for the
patient. An exploration of these factors would
help to determine a clinically relevant MID.
However, establishing a core outcome set to
monitor change in lymphoedema is a necessary
step in this process.
Conclusion
From this systematic review, the outcomes
observed to report change in lymphedema
included size, interlimb fluid ratio (BIS), dermal
thickness, tissue resistance, visible differences,
and patient-self report, with an over-emphasis
on the outcome of size. When papers looked at
outcomes beyond size, there was no agreement
for which additional outcomes were included.
The necessary or core outcome set to demon-
strate clinically relevant change in lymphedema
remains unclear. Reporting was also restricted
to the arm from wrist to axilla excluding the
hand. For each outcome used there were incon-
sistencies in the measurement tools used to cap-
ture data, protocols for their use, data analysis
and reporting. This heterogeneity of outcomes
limits the synthesis and usability of the research.
In addition, consensus was not seen for the
minimally important difference (MID) and in
view of the varied physiological effects of lym-
phoedema, it would be necessary, at a
12 R. SIERLA ET AL.
minimum, to establish a MID for both size and
BIS. Ultimately, consensus on a core outcome
set, development of prognostic outcomes and
establishing a MID for the outcome set agreed
would benefit all stakeholders in the field of
lymphedema. Widespread adoption of lymphe-
dema assessment reporting software could pro-
vide the impetus, and a framework to begin to
make these changes while encouraging a more
comprehensive and consistent approach.
Disclosure statement
The authors report no conflicts of interest.
Funding
The research received support from Sydney Research.
ORCID
Robyn Sierla https://orcid.org/0000-0002-8115-5631
Elizabeth Sian Dylke http://orcid.org/0000-0002-
7115-8142
Sharon Kilbreath https://orcid.org/0000-0002-8115-5631
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BJ. Bioelectrical impedance for monitoring the
efficacy of lymphoedema treatment programmes.
Breast Cancer Res Tr.. 1996;38(2):169–176.
64. Libanore D, Buzato E, Barufi S, Guimaraes TD,
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ragodoy device. J Phlebol Lymphol. 2011;4(1):31–33.
65. Uzkeser H, Karatay S. Intermittent pneumatic com-
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66. Dylke ES, Ward LC, Meerkin JD, Nery L, Kilbreath
SL. Tissue composition changes and secondary lym-
phedema. Lymph Res Biol. 2013;11(4):211–218.
67. Association AL. Circumferential Measurement
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lymphoedema.org.au/public/7/files/Comms/ALA_
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 CANCER INVESTIGATION 15

69. Fu MR, Ridner SH, Hu SH, Stewart BR, Cormier JN, 7. arm/or arm.mp.166365
Armer JM. Psychosocial impact of lymphedema: a 8. upper limb.mp.(15997)
systematic review of literature from 2004 to 2011. 9. upper extremity.mp.(15742)
Psychooncology.. 2013;22(7):1466–1484. 10. 7 or 8 or 9(177521)
70. Broderick JE, DeWitt EM, Rothrock N, Crane PK, 11. 6 and 10(6680)
Forrest CB. Advances in patient-reported outcomes: 12. limit 11 to (clinical trial and yr¼"1980 -Current")(612)
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2013;1(1):1015.
71. Santana MJ, Feeny D. Framework to assess the effects Pubmed search- 04/02/2016
of using patient-reported outcome measures in (("lymphoedema"[All Fields] OR "lymphedema"[MeSH
chronic care management. Qual Life Res. 2014;23(5): Terms] OR "lymphedema"[All Fields]) OR ("oedema"[All
1505–1513. Fields] OR "edema"[MeSH Terms] OR "edema"[All Fields])
72. Ridner SH, Dietrich MS. Development and validation OR ("edema"[MeSH Terms] OR "edema"[All Fields] OR
of the lymphedema symptom and intensity survey-
"swelling"[All Fields]) OR lymphoedemic[All Fields]) AND
arm. Support Care Cancer. 2015;23(10):3103–3112.
(("arm"[MeSH Terms] OR "arm"[All Fields]) OR ("upper
73. Fu MR. Breast cancer-related lymphedema: symptoms,
extremity"[MeSH Terms] OR ("upper"[All Fields] AND
diagnosis, risk reduction, and management. WJCO.
"extremity"[All Fields]) OR "upper extremity"[All Fields] OR
2014;5(3):241–247.
("upper"[All Fields] AND "limb"[All Fields]) OR "upper
74. Dylke ES, Alsobayel H, Ward LC, Liu M, Webb E,
limb"[All Fields]) OR ("upper extremity"[MeSH Terms] OR
Kilbreath SL. Use of impedance ratios to assess hand
swelling in lymphoedema. Phlebology. 2014;29(2): ("upper"[All Fields] AND "extremity"[All Fields]) OR "upper
83–89. extremity"[All Fields])) AND (Clinical Trial[ptyp] AND
75. Borthwick Y, Paul L, Sneddon M, McAlpine L, Miller ("1980/01/01"[PDAT]: "2016/12/31"[PDAT]))(617)
C. Reliability and validity of the figure-of-eight
method of measuring hand size in patients with breast
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cancer-related lymphoedema. Eur J Cancer Care
(Engl). 2013;22(2):196–201. Trials
76. Lee MJ, Boland RA, Czerniec S, Kilbreath SL.
Reliability and concurrent validity of the perometer There are 9422 results from 932577 records for your search
for measuring hand volume in women with and with- on ’lymphoedema or lymphedema or lymphoedemic or
out lymphedema. Lymphatic Res Biol. 2011;9(1): lymphedemic in Title, Abstract, Keywords or edema or
13–18. oedema in Title, Abstract, Keywords or swelling in Title,
Abstract, Keywords and (arm or upper limb or upper
extremity) in Title, Abstract, Keywords, Publication Year
Appendix 1 from 1980 to 2016 in Trials’
Medline search- 04/02/2016 Reviews
There are 144 results from 9258 records for your search on
1. swelling.mp.(40502) ’lymphoedema or lymphedema or lymphoedemic or lym-
2. Edema/or oedema.mp.(24878) phedemic in Title, Abstract, Keywords or edema or oedema
3. Lymphedema/or lymphoedema.mp.(4066) in Title, Abstract, Keywords or swelling in Title, Abstract,
4. lymphoedemic.mp. (2) Keywords and (arm or upper limb or upper extremity) in
5. 1 or 2 or 3 or 4(66113) Title, Abstract, Keywords, Publication Year from 1980 to
6. upper limb.mp. or Upper Extremity/(12859)
2016 in Cochrane Reviews’
7. arm.mp. or Arm/(79184)
8. 6 or 7(87995) Cinahl search- 04/02/2016
9. 5 and 8(1990) S8S4 AND S7 (38)
10. limit 9 to (yr¼"1980 -Current" and clinical S7S5 OR S6 (30,291)
trial, all)(354) S6"upper limb" (2,921)
S5(MH "Arm") OR "arm" OR (MH "Upper Extremityþ") (29,206)
S4S1 OR S2 OR S3 (292)
Embase search- 04/02/2016 S3"swelling" (149)
1. lymphoedema.mp. or lymphedema/9260 S2(MH "Edemaþ") OR "oedema" (168)
2. swelling.mp.88177 S1(MH "Lymphedemaþ") OR "lymphoedema" (25)
3. oedema.mp. or edema/71228 Interface - EBSCOhost Research Databases
4. lymphoedemic.mp.4 Search modes - Boolean/Phrase
5. lymphedemic.mp.3 Limiters - Published Date: 01/01/1980-31/01/2016 and
6. 1 or 2 or 3 or 4 or 5160810 clinical trials
16 R. SIERLA ET AL.

Web of Science search- 05/02/2016 iii )Simplified Frustum formula (Sitzia’s method);25,34
Volume ¼ L/4p (c1c2 þ c2c3 þ c3c4
þ … … … .c13c14 … )
Appendix 2 Where L ¼ segment length and c1c2 is the circumference
at the top and bottom of the first segment
Equations for calculating volume
iv) Numerical integration by piecewise quadratic approxi-
i)Truncated cone (Frustum method), 23,27,33,40,42 mation (Simpson’s rule of integration for volume);17
V ¼ h ðC2 þ Cc þ c2Þ =12p
Ðb
Where C ¼ top of the cone; c ¼ bottom of the cone a f ðxÞdx  Dx
3 ðy0 þ 4y1 þ 2y2 þ 4y3 þ 2y4 þ ::: þ 4yn−1 þ yn Þ

ii) Cylinder (Kuhnke formula);26,35,36 v) Unlabelled.28,44 (McKenzie and Ridner)

Volume ¼ C12 þ C22 þ C32 þ … … þ Cn2/p
Where circumference measures are taken every 4cm –
C1, C2, C3 …
 2
Voume of segment ¼ p Circumference=2p h
Segments are summed for whole arm volume, and
Circumference is the average of top and bottom circumfer-
ence of the segment

# 11 457 #10 AND #9

Indexes ¼ SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC
# 10 451,111 (TS ¼ clinical trial) AND LANGUAGE: (English)
Indexes ¼ SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC
#9 3,903 #8 AND #4
Indexes ¼ SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC
#8 222,808 #7 OR #6 OR #5
Indexes ¼ SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC
#7 191,948 (TS ¼ arm) AND LANGUAGE: (English)
Indexes ¼ SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC
#6 20,040 (TS ¼ upper extremity) AND LANGUAGE: (English)
Indexes ¼ SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC
#5 23,262 (TS ¼ upper limb) AND LANGUAGE: (English)
Indexes ¼ SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC
#4 187,996 #3 OR #2 OR #1
Indexes ¼ SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC
#3 102,632 (TS ¼ swelling) AND LANGUAGE: (English)
Indexes ¼ SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC
#2 84,861 (TS ¼ edema) AND LANGUAGE: (English)
Indexes ¼ SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC
#1 6,083 (TS ¼ lymphedema) AND LANGUAGE: (English)
Indexes ¼ SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH,ESCI, CCR-EXPANDED, IC
Timespan ¼1980-2016 (Applied to all) (457)
 Where the search terms are the same within a search engine the terms have been narrowed to one (e.g. lymphoedema/lymphedema). This has been
investigated prior to entering terms.
Where a keyword does not bring up any results (e.g. lymphoedemic) it has not been included in the search listed above.