A Systematic Review of The Outcomes Used To Assess Upper Body Lymphedema

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Cancer Investigation

ISSN: 0735-7907 (Print) 1532-4192 (Online) Journal homepage: http://www.tandfonline.com/loi/icnv20

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 phedema include:
obstruction, impairment or other deficit in the i. Measurement of volume assessed by water
lymphatics. Once established, lymphedema is a displacement; measurement of size assessed by
chronic and potentially progressive condition. flexible tape measure, and measurement of size
What starts as an increase in lymphatic fluid in and volume using a PerometerTM (an optoelec-
the tissues can lead to localised tissue changes, tronic limb volumeter). Volume may also be
most notably an increase in adipose fat and manually derived from circumferences using a
thickening of the dermis (1). There is, however, mathematical formula.
significant individual variance in the rate and ii. Measurement of the volume of extracellular fluid
extent of these soft tissue changes (2). In light of can be assessed by bioimpedance spectroscopy
the varying soft tissue effects, an unpredictable (BIS) or Tissue Dielectric Constant (TDC).
time course and only moderate reliability for iii. Measurement of changes in tissue resistance
patient self-assessment (3,4), accurate and assessed by tonometry, a pitting test and
ongoing assessment of lymphedema and its by palpation.
response to treatment is a key factor in
its management. Previous attempts at meta-analyses of
Best practice guidelines describe a range of lymphoedema treatment research cite heterogen-
subjective and objective assessment tools for eity of the outcome measures used as a barrier to
measuring lymphedema and its impact (5,6). combining data. (7–9) As it is unclear whether
Subjective approaches include self-report of the heterogeneity arises from the variety of
symptoms such as feelings of tightness and heavi- assessment tools being used, the way the
ness, assessment of skin changes, and quality of 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 (ED). Fifty-five studies from 19 different nations
establish a core set of outcomes to be used met the inclusion criteria (Figure 1).
in future lymphedema treatment research.
Furthermore, what a minimum important Data analysis
difference (MID), or a clinically significant
change in response to a treatment or progression A data extraction form was developed in
MicrosoftV Access 2013 to organise the relevant
R

of swelling for established lymphedema is


unclear. (10,11) findings prior to undertaking the review. Data
The primary aim of this systematic review is to extracted included the assessment tools used to
assess lymphedema status, as well as how
describe what measurement tools and assessment
progression or response to treatment were
methods are commonly used to assess change in
reported. For outcomes related to size, a hier-
lymphedema presentation, and how outcomes
archical approach to analysis was used in which
from the assessments are reported. The secondary
reported data were initially separated into change
aims were to explore whether a threshold for
in i) volume or ii) circumferential measurements.
change was pre-determined (a priori); what
These outcomes were then separated into further
thresholds were selected, and whether there was
domains of absolute or relative change and lastly
justification for selecting this threshold. point differences, summed differences, unilateral
comparisons, or percentage difference over time.
Methods The frequency of each outcome was tabulated. In
Literature search addition, each study was reviewed to see whether
a threshold for clinically relevant change was
Relevant studies were identified through searches stated either explicitly within the body of the text
conducted in Medline, Embase, Pubmed, Web of or within the power calculation for continuous
Science, Cinahl and Cochrane library (Appendix data. In cases where the proposed thresholds
1). Primary search terms used were ‘swelling/ referenced another publication, the original paper
oedema and lymphedema’ and ‘upper limb’. The was examined to investigate whether a rationale
search, limited to English language sources from was described for the threshold selected.
2000 to March 2016 identified an initial 9971
articles. Three authors (SK, ED and RS) screened Results
6644 titles each (including abstracts where neces-
sary) to ensure each study was screened twice for Assessment tools and measurement methods
potential eligibility. Within and across the studies reviewed, a range
Studies were included in the full paper review of measurement methods and assessment tools
if they met the following inclusion criteria: were used to quantify change in upper body lym-
phedema (Table 1). Change in limb size was
 Randomised or quasi-randomised control trials, reported for 53 of the 55 studies reviewed (Figure
prospective cohort studies over time, pre-post 2). Circumference measurements from a flexible
studies; or retrospective cohort studies tape measure were the most frequently employed
over time. approach and were used in 33 (60%) of the stud-
 Diagnosis of upper limb lymphedema with ies reviewed (11–43). However, methods for
measurable criteria set to establish the presence measurements using a tape varied widely. For
of lymphedema. example, intervals for circumference measure-
 Report a change over time or change with ments included 3 cm, 4 cm, 5 cm or 10 cm, with
intervention. starting points of either the ulnar styloid or olec-
ranon. Furthermore, only 10 of the 33 studies
One hundred and seventy-one full texts were using circumferences reported the position the
reviewed by two authors (SK and RS) and any subject was in when measures were taken. When
disagreement was reviewed by a third author reported, the positions for measurement varied,
CANCER INVESTIGATION 3

Figure 1. PRISMA flow chart.

including i) seated with the participant’s arm Submersion depth descriptions included: 45 cm
abducted to 90 degrees and resting on a measure- (40) above ulnar styloid, 50 cm (61), or ‘as close
ment board (26) or table (7, 15, 16); ii) partici- to the axilla as possible’ (47). Volume measure-
pant supine, arms by their side relaxed with ments from water displacement methods pro-
elbows straight (12,20,40); iii) participant seated, vided upper limb volume results inclusive of the
arm abducted to 30 degrees; (21) and iv) partici- hand in all but one study (40), while volumes
pant seated, elbow extended with the hand on derived from circumference or PerometryTM pre-
the ipsilateral knee (19). sented results did not.
Other tools were used to assess change in limb Other assessment tools were used as part of a
size including PerometryTM in 7 (13%) studies lymphedema assessment. Bioimpedance spec-
(10,44–49), water displacement in 20 (36%) troscopy (BIS) was used to quantify the volume
studies (7,11,18,22,23,28,33,39,40,50–60), and of extracellular fluid of the whole arm in 11
dual-energy x-ray absorptiometry (DXA) in two (22%) studies (16,24,26,33,34,44,48,57,61,63,64),
studies (4%) (15,16). Two methods of water with one study also measuring the interlimb
displacement were used to assess volume. The ratio for extracellular fluid within 10 cm seg-
ments along the arm (48). The ImpedimedV
R
standard water displacement technique measures
the volume of water displaced out of the SFB7 was used in five studies reporting the
container when the arm is submerged interlimb extracellular fluid ratio
(11,18,22,23,28,33,39,40,50,52–55,57,58,60–62). (24,34,48,57,61) and the Impedimed U400 was
The alternate method is called inverse water volu- used in three studies. Other devices used for
metry, or shortness of water, and is where a assessing extracellular fluid volume with BIS
volume calculation is made based on the change were the InBody S10 (64), and 3.0 Body
in the water level (7,51). Protocols for the water Composition Analyser (33,44), (BioSpace, Seoul,
displacement method were not described in all Korea). Tissue Dielectric Constant
papers reviewed. However in the papers where it (MoistureMeterTM) was used in two studies to
was described, it was evident that there was measure cutaneous lymphoedema (19,47).
inconsistency in volumes provided due to differ- TonometryTM was used bilaterally in two studies
ing protocols of limb submersion depth. 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 While most clinician-reported outcomes were
in two studies (28,35) One study took ultra- from objective assessment tools, subjective assess-
sound measures of the affected limb only, while ments using observation or palpation were
the second measured interlimb differences. reported in five studies. Visible changes over the
Caliper creep using the Harpenden skinfold cal- chest wall were observed from clinical photog-
liper and the line method in one study meas- raphy in one study (45). Palpated changes were
ured skin thickness in the affected limb (35). also reported, for example, using a graded assess-
Protocols differed for the points of measure- ment of pitting (45,46). The International Society
ment for all studies where Tissue Dielectric of Lymphology (ISL) grading scale for lymphe-
Constant, Tonometry, calliper measurements dema (39,51), and a grading scale proposed by
and ultrasound were used. Campisi (7) provided a rating of the severity of
Participants’ self-assessment of the impact of lymphedema based on a combination of observed
treatment was reported in 28 of the papers and palpated changes. Measurement of the breast,
reviewed (51%). Several used both a quality of chest wall or upper quadrant of the trunk were
life (QOL) tool and a symptom report tool addressed in only two studies reviewed (24,45),
(35,44–46,65). The lymphedema-specific tools and hand lymphedema was not individually
used to assess the impact of living with lymphe- assessed in any of the studies.
dema included the Lymphedema Symptom
Intensity and Distress Survey – Arm (LSIDS-A)
Outcome analysis and reporting
(24), and Lymphedema Quality of Life Tool
(LYMQOL) (10). Visual analogue or numerical For each assessment tool and measurement
scales to estimate symptom severity for items method, there was significant variance in how the
such as heaviness and tightness and pain were outcomes were analysed and reported (Figure 2).
used in 15 studies (13,15,22,26,28,32,35,37,42–44, Fifty-three studies reported change in volume or
51,55,61,65). One study reported the patient’s size from baseline to follow up. In four studies,
self-assessment of arm swelling and tissue indur- only change in the measurements of the affected
ation (pitting) (45). limb were reported (20,38,50,54), while the
6 R. SIERLA ET AL.

remainder of the studies (n ¼ 49) reported change Circumference measurements were converted
in the interlimb differences from bilateral meas- to a volume (ml) using a mathematical equation
ures, often in addition to single limb calculations. in 20 (61%) studies (11,13,17–19,21–25,27,29–32,
Changes in outcomes were reported in absolute 35,36,38,40,41,43). (Appendix 1). Inconsistencies
(cm and ml) and relative terms (percentage were identified in the formulae used to convert
and ratio). circumference data into volume. For example, the
Absolute changes in outcomes were reported different formulae used to calculate volume were
either pre- and post-intervention, or as a change included: i) truncated cone (a.k.a. frustum
over time (n ¼ 41). Pre and post intervention method) (19,23,29,36,38), which was the most
results were quantified using: a single limb cir- commonly used formula; ii) cylinder (a.k.a.
cumference or an interlimb circumference differ- Kuhnke formula) (22,31,32); iii) simplified
ence at a single location (14,16,28,39); single limb Frustum formula; (21,30) iv) numerical integra-
or interlimb summed circumference difference tion by piecewise quadratic approximation (a.k.a.
(14,37,42); single-arm volume or inter-limb vol- Simpson’s rule of integration for volume) (13)
ume difference (7,10,17–19,22,24,25,28–33,35,36, and v) one other unlabelled formula for volume
38,40,43,44,47,48,50,51,53,54,57–59,61). Where (24,40) (Appendix 2).
outcomes were reported as a change over time BIS was used in 11 studies (15,16,24,26,33,34,
they were quantified by: reduction in a single 44,48,57,61,64) of which all but one reported
limb or interlimb summed circumference change in size (64). For measurements using BIS,
difference (12,14,37,42) and reduction in a the interlimb extracellular fluid volume was pre-
single limb or interlimb volume difference sented as a ratio in five studies (24,34,48,57,61)
and converted to an L-DexV score in three
R
(15–17,21,25,35,39,40,43,44,51,60). The difference
in volume between the affected and contralateral (15,16,26) Of the remaining three studies, one
limb was variously labelled ‘volume excess or VE’ reported results by ‘arbitrary bioimpedance
(43), ‘absolute oedema volume’ or ‘absolute dif- machine units’ (44), one cited results in an
ference’ (13), ‘excess volume or EV’ (32), or unpublished table (64), and the third presented
‘oedema volume’ (51). results, however, it was unclear what data were
Relative changes in outcomes were reported representing (33). As no reference was made to
by percentage or as a ratio (n ¼ 36). These either interlimb differences or interlimb ratios, it
data were reported pre and post-intervention is assumed these three studies were reporting sin-
with the interlimb difference represented gle-limb results. Single-limb results were also
limb  unaffected limb reported for ultrasound (35) and calliper (35)
by percentage ðaffected unaffected limb 100Þ (7,10,
measures of dermal thickness, while Tonometry
11,17–19,25,30,31,35,40,41,43,45–47,49,51,57–59,
(44,60), Tissue dielectric constant (19,47), and in
61,62); or ratio (13,48); or as a change
one instance, ultrasound (28), were presented as
(percentage reduction) over time
volume difference time 2 – interlimb volume difference time 1
an interlimb difference.
ðinterlimb interlimb volume difference time 1 100Þ:
(7,10,17–19,25,31,35,41,43,45,46,49,51,59,62). An
Thresholds for change
interlimb ratio was derived from summed cir-
cumferences (13,21); and a percentage was Expected or required thresholds for change due to
derived from (i) summed circumferences; (11) treatment given were explicitly established a priori
(ii) largest circumference difference (11) or (iii) in nine studies (14,17,21,29,44,45,48,57,59). In 10
volume difference (7,10,11,14,17–19,25,30,31,35, studies (13,15,16,20,23,25,26,31,45,51), the thresh-
40,41,43,45–47,49,51,57–59,61,62). Of the studies old for change was reported within power calcula-
reporting change in size or volume (n ¼ 53), tions, with two established post-priori (10,27).
results were presented pre- and post-intervention Notably, the required thresholds for change were
only in 15 studies (28%), by change over time in not consistent (Table 2). Of the 21 studies in
two studies (4%), and by both in 36 studies which thresholds for change were set a priori, 20
(68%) (Table 1). different thresholds were reported. For randomised
CANCER INVESTIGATION 7

Table 2. Criteria reported to signify a significant change.


Intervention Control Study powered for change Threshold set a priori
Ahmed Omar 2011 (12) LLLT (n ¼ 25) Sham LLLT (n ¼ 25)
Andersen 2000 (13) Standard treatment (compres- Standard treatment Designed to detect a 20%
sion sleeve, education, (compression sleeve, L/E volume# over 3 m with
exercise) plus manual lymph education, exercise) p  0.05 Power ¼0.90.
drainage (MLD) (n ¼ 20) no MLD (n ¼ 22) Sample size of 42 required
Bergmann 2014 (43) Bandaging, exercise, plus Bandaging, exercise,
MLD (n ¼ 28) no MLD (n ¼ 29)
Bordin 2009 (50) Electromechanical device –
passive exercise and
stretches (n ¼ 25)
Carati 2003 (44) LLLT (two treatment LLLT (sham cycle then one 200 ml # in L/E volume
cycles) (n ¼ 33) treatment cycle) (n ¼ 28)
Cassileth 2013 (14) Acupuncture (n ¼ 33) if 3/27 achieve 30% # in
comparative arm
circumference
Cormie 2013 (15) High load resistance Low load resistance exercise a level of 0.05 (5% change)
exercise (n ¼ 17) (crossover design with for a final sample of
washout period) 17. Power ¼ 80%
Cormie 2013 (16) High load resistance exercise Control (n ¼ 19) Significance acknowledged as
(n ¼ 22); Low load resistance 5% (from Schmitz study) but
exercise (n ¼ 21) set to detect 2% for power
calculation of 80% for sam-
ple size of 62.
Damstra 2009 (51) Low pressure bandaging High pressure bandaging To achieve a power of 80%
20-30 mmHg (n ¼ 18) 44-58 mmHg (n ¼ 18) with 95% reliability a sam-
ple of 741 for 10%# or 119
for a 20% # in volume.
Damstra 2009 (7) Lympho-venous anasto-
mosis (n ¼ 11)
Dayes 2013 (17) Decongestive Lymphatic Compression garment 40% # in L/E volume in a
Treatment (DLT) MLD, (n ¼ 39) garment over 6 weeks. 20%
bandaging treatment cycle # reduction in L/E volume
with compression garment with DLT over and above
on completion (n ¼ 56) that achieved in garment
De Godoy 2015 (52) Compression garment
(novel) (n ¼ 66)
De Godoy 2013 (53) DLT (n ¼ 66)
Didem 2005 (18) DLT including MLD, DLT including bandaging,
bandaging, elevation elevation and exer-
and exercises (n ¼ 27) cises (n ¼ 26)
Fife 2012 (19) Advanced intermittent Standard IPC (n ¼ 18)
pneumatic compression
(IPC) device (n ¼ 18)
Fong 2014 (20) Qigong (n ¼ 11) Control (n ¼ 12) 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
Forner-Cordero 2010 (32) DLT (n ¼ 171)
Godoy 2012 (54) Active exercise – pulley Active exercise – pulley
system with sleeve (n ¼ 20) system without
sleeve (crossover)
Gothard 2004 (45) Vitamin E and Placebo (n ¼ 33) 100 patients randomised was
Pentoxyfylline (n ¼ 35) 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%)
Gothard 2004 (46) Hyperbaric oxygen 20% # in arm volume at
therapy (n ¼ 21) 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 Control Study powered for change Threshold set a priori
Gradalski 2015 (21) DLT - with MLD Compression bandag- 200ml - primary end point
(Vodder) (n ¼ 25) ing (n ¼ 26) below which the two
treatments used would be
considered as equivalent
Gurdal 2012 (36) DLT (n ¼ 15) IPC þ SLD (n ¼ 15)
Haghighat 2010 (55) Modified DLT þ IPC (n ¼ 56) DLT (n ¼ 56)
Jeffs 2013 (10) Self-care (with compression Self-care (with compression Post-priori. For a robust
garment) þ home garment) (n ¼ 12) study to detect 5%# in
exercises (n ¼ 11) L/E volume. Power ¼80%,
p  0.05. Sample size to
achieve this ¼100 in
each group.
Johansson 2013 (57) Weightlifting programme 3/7
– 8 weeks (n ¼ 23)
Johansson 2014 (47) Twice daily sessions of Control (n ¼ 14) 5% between group difference
water based exercise – considered clinically
8 weeks (n ¼ 15) significant
Johansson 2005 (61) Low resistance exercises with Low resistance exercises
compression sleeve (n ¼ 31) without compression sleeve
(cross-over)
Jonsson 2009 (58) Pole walking – single
episode (n ¼ 26)
Jonsson 2014 (59) Pole walking – 3–5/7 for 9% # in L/E volume consid-
8 weeks (n ¼ 23) ered clinically important;
3% #L/E volume consid-
ered clinically meaningful
according to clin-
ical experience
Kaviani 2006 (37) LLLT (n ¼ 4) LLLT sham (n ¼ 4)
Kim 2010 (38) Active resistance DLT (n ¼ 20)
exercise þ DLT (n ¼ 20)
King 2012 (22) DLT with garment DLT with bandaging
(n ¼ 10) (n ¼ 11)
Kozanoglu 2009 (42) Intermittent pneumatic LLLT (n ¼ 23)
compression (IPC)
(n ¼ 24)
Letellier 2014 (11) Home exercise programme Home exercise pro-
plus water based exercise gramme (n ¼ 12)
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 Single session MLD no 10%# in BIS ratio(63)
lymphoedema (n ¼ 15) lymphoedema (n ¼ 15)
164 ml# in limb volume (69)
McKenzie 2003 (40) Exercise programme (n ¼ 7) Control (n ¼ 7)
McNeely 2004 (23) Compression bandaging Compression bandaging Sample size needed 42
with MLD (n ¼ 25) no MLD (n ¼ 25) (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
Mondry 2004 (39) DLT (n ¼ 20)
Ridner (24) IPC– arm (n ¼ 21) IPC– arm and trunk
(n ¼ 21)
Shaw 2007 (25) Weight reduction Control (n ¼ 10) Intention to recruit 50 based
programme (n ¼ 11) 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 Control Study powered for change Threshold set a priori
Shaw 2007 (31) Weight reduction programme Control (n ¼ 15) Sample size determined with
through reduced energy intention to recruit 60–20 in
intake (n ¼ 19) vs Weight each group based on
reduction programme - assumptions that dietary
low fat (n ¼ 17) 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.
Singh 2015 (26) Moderate load resistance Moderate load resistance Sample size calculations - to
exercise with compres- exercise without detect a change of 10 units
sion (n ¼ 25) compression (crossover) for L-Dex, Power ¼ 80%
and significance at 5%, 2-
tailed, 22 partici-
pants required.
Sitzia 2002 (27) MLD (n ¼ 15) Simplified lymphatic Post-priori: % change in
drainage (n ¼ 13) 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.
Smith 2014 (34) Acupuncture (n ¼ 10) Control (n ¼ 10)
Smykla 2013 (49) Kinesiotape (n ¼ 20) vs Quasi- DLT (n ¼ 23)
kinesiotape (n ¼ 22)
Szuba 2002 (60) DLT with IPC (n ¼ 12) DLT (n ¼ 11)
Tsai 2009 (33) DLT with bandage (n ¼ 21) DLT with kinesiotape
(n ¼ 20)
Uzkeser 2013 (65) DLT with IPC (n ¼ 12) DLT (n ¼ 13)
Uzkeser 2015 (28) DLT with IPC (n ¼ 16) DLT with MLD (n ¼ 15)
Vignes 2013 (29) DLT – volume reduction at A L/E-volume # after 4 d
4 d vs 11 d in treat- >75% of the total obtained
ment (n ¼ 129) after 11 d was considered
clinically relevant to con-
sider shortening
DLT duration
Wilburn 2006 (30) IPC and garment (n ¼ 10) SLD self-massage and
garment (cross-over)
Williams 2002 (35) MLD and garment (n ¼ 31) SLD self-massage and
garment (cross-over)
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.

controlled trials, the thresholds for change varied obtained after 11 d of treatment. Only three studies
among 5%, (16) 20%, (45) or 200 m (44) volume cited other work as informing their selection of
change or a 10 L-Dex unit change using BIS (26). clinically relevant change: a 5% (15), or 200 ml vol-
Contrastingly in parallel intervention studies, the ume change (21), and a 10-point change in BIS
most common threshold set for expected change ratio or 164 ml volume change (48).
was 5% change in volume or between-group differ-
ence (10,15,16,47). For those studies which used a
Discussion
parallel or cross-over design, the threshold related
to the additional benefit obtained from one inter- Across the research, secondary upper limb
vention over another. For example, Wilburn (30) lymphoedema is assessed by a range of tools and
stated a priori that the duration of treatment was outcome measures. While outcomes included
clinically relevant if the decrease in lymphedema interlimb fluid differences, dermal thickness and
volume was >75% of the total decrease in volume 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- introduced by differences in participant position-
ment effect. The multitude of methods under- ing, intervals and locations of circumference
taken to measure, analyse and report the various measurement, as well as differing formulas used
values reveal no clear picture of what method for converting circumference to volume, and dif-
should be used, or more importantly, the ferences in terminology used for reporting the
minimally important difference. The absence of outcomes. Although outcomes are most
agreed-upon thresholds for change and the commonly reported as volume, these were often
inconsistencies observed impede the evaluation converted from raw circumference data (cm) to
of lymphedema treatments, with several volume (ml) before being expressed as interlimb
meta-analyses citing heterogeneity of results difference as a percentage (%). In this example,
limiting opportunities for data summation (7–9). the conversion to volume is an unnecessary
Furthermore, due to the progressive nature of double handling of data reducing the specificity
lymphedema, simply looking at limb size is not of the final outcome reported. The primary issue
sufficient to assess the impact of a treatment; its for data synthesis among studies, however, is the
assessment requires a heterogeneous group of absence of one consistent outcome that can be
outcome measures to appropriately capture its compared across studies. As such, the authors
multidimensional nature (66). Currently, the recommend for that, as a minimum, one size-
combination of outcomes required to capture based interlimb outcome measure expressed in
meaningful change in a lymphedematous limb is relative terms be included in all future research
unclear. This review highlights where agreement (5,67). The use of a relative outcome enables
is needed including i) the methodology for limb combining of data, regardless of the assessment
size assessment; ii) inclusion of other tools to tool or measurement method used.
assess specific dimensions of lymphedema; iii) The reliance on changes in size only may
upper body regions that require reporting and, under-estimate the impact of treatment or miss
iv) minimally important difference. fundamental changes resulting from treatments.
Both within and across studies, a range of Agreement was not evident for what outcome
measurement tools and reporting methods were measures were necessary to ensure all relevant
used to capture the same outcome, size, with changes are captured. Clinical tools are available
both absolute and relative changes derived from to capture many dimensions of change (Figure
the same data being reported in multiple ways 3), while these tools were used in some papers
(13,17,19,25). There were inconsistencies in how the rationale for when and why they were
size data are captured and analysed. Variance was included was not elucidated. Bioimpedance
CANCER INVESTIGATION 11

spectroscopy reliably measures the volume of current review, we looked at whether a threshold
extracellular fluid of which lymph is a major for change was set a priori in the studies
component (4,68). Ultrasound and calliper meas- reviewed. All thresholds established a priori were
ures assess dermal thickening, and palpation or objective measures of size or BIS, and primarily
TonometerTM assess tissue resistance. reduction in size (Table 2). There was no consist-
Understanding which treatments impact on der- ency evident among the thresholds set a priori
mal thickness or tissue resistance, for example, with percentage reductions ranging from 2% (16)
may assist in the prescription of more targeted to 60% (17). Only one study used a statistically
treatment approaches. To assess the impact of derived threshold based on the fluctuation of
this condition patient-reported outcomes related lymphedema over time (48). While a few studies
to symptoms, function and psychosocial well- have considered statistical significance, thresholds
being are also necessary (69) but were reported for change that are clinically significant, that is,
in only half of the studies reviewed. Patient- minimum important difference (MID), are yet to
reported outcomes are gaining recognition for be determined or discussed. Future papers would
their importance in health-related research (70), benefit from selecting a threshold to represent
particularly for chronic disease management (71). the MID along with a rationale for why this
The patient-reported outcomes observed were threshold was selected. It is currently unknown
primarily focussed on the assessment of symp- what amount of change is needed to make a
toms such as discomfort, using a visual assess- significant impact for the patient, and whether in
ment scale. Validated and reliable questionnaires fact size reduction is the primary goal for the
are available that can be used for self-report patient. An exploration of these factors would
which extend beyond symptom report to the help to determine a clinically relevant MID.
effects on lymphoedema on quality of life and However, establishing a core outcome set to
function, including the LSIDS-A (72) and monitor change in lymphoedema is a necessary
LYMQOL (10) found in this review. Agreement step in this process.
on the use of one of these or a similar standar-
dised measure for PROs would also improve
Conclusion
consistency in reporting.
Outcome reporting for upper body lymphe- From this systematic review, the outcomes
dema secondary to breast cancer has been con- observed to report change in lymphedema
fined to the arm from the wrist to axilla. included size, interlimb fluid ratio (BIS), dermal
Although the search terms for this systematic thickness, tissue resistance, visible differences,
review included the terms ‘upper extremity’ and and patient-self report, with an over-emphasis
‘upper limb’, hand lymphedema was not reported on the outcome of size. When papers looked at
in any of the included papers. There has been a outcomes beyond size, there was no agreement
paucity of instruments available to objectively for which additional outcomes were included.
measure size change in the hand (73), although The necessary or core outcome set to demon-
recent investigations have demonstrated that BIS strate clinically relevant change in lymphedema
can be reliably used for assessment of hand remains unclear. Reporting was also restricted
lymphedema (74) and techniques for hand to the arm from wrist to axilla excluding the
volume and circumference measurement have hand. For each outcome used there were incon-
been reported (75,76). sistencies in the measurement tools used to cap-
There has been little to no attention paid to ture data, protocols for their use, data analysis
clinically significant change in established lym- and reporting. This heterogeneity of outcomes
phedema for any outcome measure. Only one limits the synthesis and usability of the research.
study reviewed fluctuation of lymphedema over In addition, consensus was not seen for the
different periods of time to determine the stand- minimally important difference (MID) and in
ard error of measurement to inform ‘real change’ view of the varied physiological effects of lym-
from that of normal fluctuation (4). In the phoedema, it would be necessary, at a
12 R. SIERLA ET AL.

minimum, to establish a MID for both size and for post-breast cancer lymphedema. Curr Breast
BIS. Ultimately, consensus on a core outcome Cancer Rep. 2013;5(2):134–144.
7. Damstra RJ, Voesten HG, van Schelven WD, van der
set, development of prognostic outcomes and
Lei B. Lymphatic venous anastomosis (LVA) for treat-
establishing a MID for the outcome set agreed ment of secondary arm lymphedema: a prospective
would benefit all stakeholders in the field of study of 11 LVA procedures in 10 patients with breast
lymphedema. Widespread adoption of lymphe- cancer related lymphedema and a critical review of
dema assessment reporting software could pro- the literature. Breast Cancer Res Treat. 2009;113(2):
199–206.
vide the impetus, and a framework to begin to
8. Finnane A, Janda M, Hayes SC. Review of the
make these changes while encouraging a more evidence of lymphedema treatment effect. Am J Phys
comprehensive and consistent approach. Med Rehabil. 2015;94(6):483–498.
9. McNeely ML, Peddle CJ, Yurick JL, Dayes IS, Mackey
JR. Conservative and dietary interventions for cancer-
Disclosure statement related lymphedema: a systematic review and meta-
The authors report no conflicts of interest. analysis. Cancer. 2011;117(6):1136–1148.
10. Jeffs E, Wiseman T. Randomised controlled trial to
determine the benefit of daily home-based exercise in
Funding addition to self-care in the management of breast
The research received support from Sydney Research. cancer-related lymphoedema: a feasibility study.
Support Care Cancer. 2013;21(4):1013–1023.
11. Letellier ME, Towers A, Shimony A, Tidhar D. Breast
ORCID cancer-related lymphedema: A randomized controlled
pilot and feasibility study. Am J Phys Med Rehabil.
Robyn Sierla https://orcid.org/0000-0002-8115-5631
2014;93(9):751–759.
Elizabeth Sian Dylke http://orcid.org/0000-0002-
12. Ahmed Omar MT, Abd-El-Gayed Ebid A, Morsy AM.
7115-8142
Treatment of post-mastectomy lymphedema with laser
Sharon Kilbreath https://orcid.org/0000-0002-8115-5631
therapy: double blind placebo control randomized
study. J Surg Res. 2011;165(1):82–90.
13. Andersen L, Hojris I, Erlandsen M, Andersen J.
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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
Cochrane search- 04/02/2016
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)


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

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