incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis

500 www.thelancet.com/oncology Vol 14 May 2013

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Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis Tracey DiSipio, Sheree Rye, Beth Newman, Sandi Hayes

SummaryBackground The body of evidence related to breast-cancer-related lymphoedema incidence and risk factors has substantially grown and improved in quality over the past decade. We assessed the incidence of unilateral arm lymphoedema after breast cancer and explored the evidence available for lymphoedema risk factors.

Methods We searched Academic Search Elite, Cumulative Index to Nursing and Allied Health, Cochrane Central Register of Controlled Trials (clinical trials), and Medline for research articles that assessed the incidence or prevalence of, or risk factors for, arm lymphoedema after breast cancer, published between Jan 1, 2000, and June 30, 2012. We extracted incidence data and calculated corresponding exact binomial 95% CIs. We used random eff ects models to calculate a pooled overall estimate of lymphoedema incidence, with subgroup analyses to assess the eff ect of diff erent study designs, countries of study origin, diagnostic methods, time since diagnosis, and extent of axillary surgery. We assessed risk factors and collated them into four levels of evidence, depending on consistency of fi ndings and quality and quantity of studies contributing to fi ndings.

Findings 72 studies met the inclusion criteria for the assessment of lymphoedema incidence, giving a pooled estimate of 16·6% (95% CI 13·6–20·2). Our estimate was 21·4% (14·9–29·8) when restricted to data from prospective cohort studies (30 studies). The incidence of arm lymphoedema seemed to increase up to 2 years after diagnosis or surgery of breast cancer (24 studies with time since diagnosis or surgery of 12 to <24 months; 18·9%, 14·2–24·7), was highest when assessed by more than one diagnostic method (nine studies; 28·2%, 11·8–53·5), and was about four times higher in women who had an axillary-lymph-node dissection (18 studies; 19·9%, 13·5–28·2) than it was in those who had sentinel-node biopsy (18 studies; 5·6%, 6·1–7·9). 29 studies met the inclusion criteria for the assessment of risk factors. Risk factors that had a strong level of evidence were extensive surgery (ie, axillary-lymph-node dissection, greater number of lymph nodes dissected, mastectomy) and being overweight or obese.

Interpretation Our fi ndings suggest that more than one in fi ve women who survive breast cancer will develop arm lymphoedema. A clear need exists for improved understanding of contributing risk factors, as well as of prevention and management strategies to reduce the individual and public health burden of this disabling and distressing disorder.

Funding The National Breast Cancer Foundation, Australia.

IntroductionLymphoedema after breast cancer is characterised by regional swelling, typically in one or both arms, due to excess accumulation of protein-rich fl uid in body tissues.1 The adverse consequences of lymphoedema are well known, and cause much mor bidity. Arm lymphoedema, and its associated symptoms, such as pain, heaviness, tightness, and decreased range of motion, impede daily function and adversely aff ect gross and fi ne motor skills, with negative ramifi cations for work, home, and personal care functions, as well as recreational and social relation-ships.2 The appearance of a swollen and sometimes disfi gured limb provides an ever-present reminder of breast cancer, which can contribute to anxiety, depres-sion, and emotional distress in aff ected women.3 Fur-thermore, preliminary fi ndings show that lymphoedema might also lead to shortened survival.4 In view of the increasing incidence of breast cancer worldwide, understanding the incidence of subsequent secondary lymphoedema and its associated risk factors is clearly of public health importance.

Individual studies report arm lymphoedema in up to 94% of patients with breast cancer,5 with the wide variation (as low as 0%) in reported results an indication of diff erences in study design, diagnostic methods and criteria used, and timing of lymphoedema measurement with respect to breast cancer diagnosis and treatment.6 Some estimates sug gest that about 20% of women will develop arm lymphoedema after breast cancer—this estimation is the average incidence of studies that have been included in several systematic reviews of lymphoedema after breast cancer.7–9 However, the average incidence of a group of studies does not take into account factors that are known to aff ect detection rates, such as study design or timing and method of lymphoedema assessment. How common such lymphoedema is after breast cancer is, therefore, unclear. Furthermore, our understanding of acquired and pre-existing risk factors is imperfect. Although more extensive treatment and a higher body-mass index have long been thought to be the major risk factors for the development of lymphoedema, advances in treatment over the past 10–15 years raise

Lancet Oncol 2013; 14: 500–15

Published OnlineMarch 27, 2013

http://dx.doi.org/10.1016/S1470-2045(13)70076-7

See Comment page 442

School of Public Health and Social Work, Institute of Health

and Biomedical Innovation, Queensland University of Technology, Queensland,

Australia (T DiSipio PhD, S Rye MAppSc,

Prof B Newman PhD, S Hayes PhD)

Correspondence to:Dr Tracey DiSipio, School of

Public Health and Social Work, Faculty of Health, Queensland

University of Technology, Victoria Park Road, Kelvin Grove,

QLD 4059, [email protected]

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www.thelancet.com/oncology Vol 14 May 2013 501

questions about whether associations between the risk of lymphoedema and these characteristics, as well as other personal, treatment, and behavioural characteristics, have changed.

The body of evidence relating to the incidence of arm lymphoedema after breast cancer has grown substantially and has improved in quality during the past decade, now including fi ndings from several prospective cohort studies. We therefore did this systematic review and meta-analysis to provide the most up-to-date estimate of the incidence of arm lymphoedema after breast cancer. Also, although the strength of treatment-related risk factors has been assessed in a 2009 meta-analysis,10 it is im portant to also consider the strength and consistency of the association between lymphoedema and other non-treatment-related risk factors, as well as timely to update fi ndings regarding treatment-related risk factors.

MethodsSearch strategy and selection criteriaWe did a systematic review to identify all studies ad-dressing the incidence of, prevalence of, or risk factors for breast-cancer-related arm lymphoedema. We did a comprehensive search of databases including Academic Search Elite, Cumulative Index to Nursing and Allied Health, Cochrane Central Register of Controlled Trials (clinical trials), and Medline to identify studies published be tween Jan 1, 2000, and June 30, 2012, that included women who had undergone surgery for breast cancer. The search terms included keywords for breast cancer (“breast” and “cancer” or “onco*”, or “neoplasm*”), lymphoedema (“lymphoedema” or “lymphedema”), and the outcomes of interest (“incidence”, “prevalence”, “risk factor”, or “prognosis”).

Eligibility criteria for inclusion of studies in this review and meta-analysis fell into six categories. Type of study: published research articles were included; review papers, meta-analyses, editorial or comment papers, case re-ports, and case series were excluded, as were randomised controlled trials that did not report lymphoedema at baseline or lymphoedema for the control group sep-arately. Patient characteristics: studies of female patients with unilateral breast cancer were included; studies of patients with bilateral breast cancer, primary lymph-oedema, or metastatic disease were excluded. Diagnosis of lymphoedema: self-reported swelling was the only symptom taken as an indication of self-reported lymphoedema; studies that reported the incidence of lymphoedema on the basis of only multiple symptoms (eg, “do you have pain, tingling, or weakness of the arm?”) were excluded, because these symptoms are common irrespective of lymph oedema status,11 and the inclusion of such symptoms might therefore lead to an overestimation of lymph oedema incidence. All objective methods of diagnosing lymphedoema were included. Outcome: incidence of, prevalence of, or risk factors for secondary lymphoedema were included—in the absence

of pretreatment lymph oedema status, prevalence was thought to be a reasonable estimate of incidence because the proportion of women with lymphoedema before surgery for breast cancer has been reported to be very low.12,13 Time period: outcome data measured within 3 months of diagnosis or surgery were excluded because arm-related changes during this timeframe were considered potentially indicative of an acute treatment-related response. Language and origin: we included studies available from all locations with reports written in English; non-English-language papers, when translations were unavailable, were excluded.

Data extractionOne investigator (TD) selected articles that potentially met our inclusion criteria on the basis of their titles and abstracts. Full articles were then retrieved for a more detailed assessment. We developed a data abstraction sheet to collect necessary information to establish the level of evidence, study quality, and available outcome and risk factor details. From every included study, one investigator (TD) extracted data for study location (country), study design, sample size, time since breast cancer diagnosis, method of lymphoedema assessment, defi nition of lymphoedema, incidence or prevalence of lymphoedema, and any risk factor information. Study designs included randomised controlled trials, cross-sectional, prospective cohort, retrospective cohort, and case–control studies (case–control studies were only included for risk factor analysis). For our meta-analysis of incidence, we recorded results from randomised controlled trials assessing an exercise intervention: we included baseline data for the intervention groups and all data (including baseline date) for the control groups. Lymphoedema measurement refers to the technique used to defi ne the presence of lymphoedema and included bioimpedance spectroscopy, arm circum ferences, water displacement or perometry (optoelectronic volumeter), lymphoscintigraphy, clinician diagnosis, and patient-reported diagnosis by a clinician or self-reported swelling.

We categorised all studies that analysed the incidence of arm lymphoedema into levels of evidence, on the basis of study design, using levels of evidence (Prognosis column) defi ned by the Australian National Health and Medical Research Council (NHMRC).14 Two investigators (TD, SR) independently categorised each study with disagreements resolved through discussion with a third assessor (SH) to attain consensus.

We assessed the presence of publication bias using funnel plots by precision, Egger’s Test of the Intercept,15 and Duval and Tweedie’s trim and fi ll procedure (data not shown).16 Funnel plots were analysed for the overall incidence and subgroup random eff ects models (relating to sentinel-lymph-node biopsy compared with axillary-lymph-node dissection) by plotting the event rate against the inverse of the SE. The funnel plot was symmetrical about the summary eff ect, with larger studies at the top

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and smaller studies at the bottom, indicating no clear evidence of publication bias. Analysis with Egger’s Test of the Intercept suggested that the intercept of the regression line approached the origin, which is indicative of no or low publication bias (intercept −0·82; 95% CI −3·6 to 2·01; p=0·56). The Duval and Tweedie’s trim and fi ll procedure also suggested no publication bias from potentially missing studies.

Two investigators (TD, SR) independently assessed each risk factor study for methodological quality using a 14-item standardised checklist of predefi ned criteria (panel) modifi ed from an established criteria list for systematic reviews.17–19 Similar adaptations have been used to review studies on lymphoedema and quality of life in breast cancer survivors.20,21 Each item of a selected study was assigned one point, with the highest possible score for any one study being 14. Although all 14 indicators were used equally, criteria specifi c to follow-up were included in the checklist, hence pro spective cohort studies were assigned extra points. Studies scoring more than 10 points (>70% or more of the maximum attainable score) were rated as high quality, studies scoring 7–9 points were rated as moderate quality, and studies scoring 6 or fewer points (lower than

50% of maximum attainable score) were regarded as low quality.17–19 Disagreement between the investigators was again resolved with the aid of a third assessor (SH). Findings for each risk factor were collated into four levels of evidence, depending on consistency (ie, asso ciation in the same direction), quality, and quantity of studies. Each study was also classifi ed according to the NHMRC Levels of Evidence; the Aetiology column was used in most cases except for exercise or surgical inter vention trials, in which case we used the Intervention column.14

Statistical analysisThe main outcome of interest for this analysis was overall cumulative incidence (%) of arm lymphoedema after diagnosis of or treatment for breast cancer, which was abstracted from the published reports of incidence or prevalence; exact binomial 95% CIs were subsequently calculated. When incidence was presented separately by treatment (eg, sentinel-lymph-node biopsy vs axillary-lymph-node dissection), we calculated an overall inci dence for the study using data from the reports. For each risk factor, we abstracted odds ratios, hazard ratios, or risk ratios and associated 95% CIs, based on unadjusted results for randomised controlled trials and adjusted estimates obtained from multivariate analyses (ie, controlled for at least one other factor) for other study designs. Odds ratios tend to overestimate relative risk;22 however, the clinical inter pretation of fi ndings remains similar unless prevalence of the disorder under investigation is greater than 30%.23 When study results were not appropriately presented (such as mean arm volume change presented without a threshold for defi ning lymphoedema, p values but no odds ratios presented for risk factors, or odds ratios presented for risk factors without CIs), we contacted the investigators of the studies (n=5) but were unable to provide results needed for inclusion in the meta-analysis.

In the absence of a diagnostic gold standard, and because some studies presented more than one esti-mation of incidence, a hierarchy of decisions was established to assess which result to include in the overall meta-analysis. For timing, the result at or closest to 2 years after diagnosis was considered the most appropriate because most patients usually present by this time.6,24,25 For studies that used more than one method of arm lymphoedema assessment, when available, results from objective circumference measurements were abstracted (because this is the most common method used in clinical practice),26 followed by perometry (because it assesses size diff erence between limbs, similar to circumferences), followed by bioimpedance spectroscopy (an objective and validated measure27), and then self-report. When incidence was presented for more than one diagnostic criterion, incidence data abstracted for inclusion in the meta-analysis showed the most common diagnostic criteria used by the studies included in the review (specifi cally, ≥2 cm diff erence between limbs for cir cumferences and ≥10% for perometry).

Panel: Criteria for assessment of the methodological quality of studies (risk factors)

Criteria were scored as positive (suffi cient information and a positive assessment), negative (suffi cient information but potential bias due to inadequate design or conduct), or unclear (insuffi cient information).

Study populationA Description of target or source populationB Description of relevant inclusion and exclusion criteriaC Description of study population

ResponseD Response ≥75%E Information on non-responders versus responders

Follow-upF Prospective data collectionG Follow-up ≥6 monthsH Dropouts or loss to follow-up ≤20%I Information on participants who completed the trial

versus those who dropped out or were lost to follow-up

TreatmentJ Treatment in study population was described

Outcome measuresK Standardised assessment of relevant outcome measures

Analysis and data presentationL Frequencies of most important outcome measuresM Appropriate analysis techniquesN Suffi ciently large study population (≥100 people per study

group)

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We used a random eff ects model to produce a pooled overall estimate for lymphoedema incidence and inci-dence estimates that allowed for comparison within lymphoedema measurement (bioimpedance spectros-copy, clinical diagnosis, circumferences, perometry, self-reported diagnosis, self-reported swelling, and multiple methods), time since diagnosis (3 months to <6 months, 6 months to <12 months, 12 months to <24 months, 2 years to <5 years, ≥5 years), and extent of axillary surgery (sentinel-lymph-node biopsy or axillary-lymph-node dissection). We used Comprehensive Meta-analysis (version 2) for statistical analyses.28

Role of the funding sourceThe study sponsor had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to the data in the study and had fi nal responsibility for the decision to submit for publication.

ResultsWe identifi ed 398 potentially relevant citations, of which 79 were included in our analysis (fi gure 1).

Most studies were either prospective or cross-sectional, but we also identifi ed randomised control trials and retrospective cohort studies, nearly half of studies were from North America, and the most common method of lymphoedema measurement was arm circumference; timing of measurements varied greatly, ranging from 3 months to 20 years after diagnosis (tables 1 and 2).

Incidence of arm lymphoedema following breast cancerWe calculated a pooled estimate for arm lymphoedema incidence of 16·6% (95% CI 13·6–20·2) using data abstracted from 72 studies of 29 612 women with breast cancer (table 1). Incidence ranged between 8·4% and 21·4%, with prospective cohort studies giving the highest estimate and retrospective cohort studies giving the lowest (table 1).

The lowest incidence was in the UK and the highest was in Australasia. The highest estimates were reported by studies that used more than one measure to classify lymphoedema, whereas the one study31 that classifi ed lymphoedema according to lymphoscintigraphy reported the lowest incidence (table 1). Incidence of a clinical

398 individual studies identified and screened

286 excluded after assessment of abstracts and titles

112 full-text articles for eligibility

33 articles excluded 7 duplicate or secondary analyses 3 recored pre-operation incidence only 19 did not meet eligibility criteria 3 simply assessed lymphoedema 1 was done more than 30 years ago

79 articles included in review (74 incidence and 31 risk factors)

72 studies on incidence*29 studies on risk factors†

Figure 1: Flow diagram of study selection for inclusion in this review and meta-analysis*We included 74 articles, which presented results of 72 studies (two studies were each presented in two articles). †We included 31 articles, which presented results of 29 studies (two studies were each presented in two articles).

Included studies (n)

Incidence (%; 95% CI)

Pooled estimate

All studies 72 16·6 (13·6–20·2)

Prospective cohort studies 30 21·4 (14·9–29·8)

Randomised clinical trial 7 10·4 (7·9–13·5)

Retrospective cohort 10 8·4 (5·4–12·8)

Cross-sectional studies 25 17·7 (13·8–22·4)

Location of study

Asia 4 18·0 (10·2–29·8)

Australasia 7 21·5 (15·0–29·8)

Europe 17 14·2 (10·9–18·4)

Middle East 1 17·5 (13·9–21·8)

North America 32 21·0 (15·1–28·5)

South America 3 13·7 (8·1–22·2)

UK 8 8·4 (5·1–13·6)

Axillary surgery

SLNB 18 5·6 (6·1–7·9)

ALND 18 19·9 (13·5–28·2)

Measurement method*

Lymphoscintigraphy 1 5·0 (1·6–14·4)

Bioelectrical impedance 3 15·9 (4·6–42·6)

Self-reported clinical diagnosis 5 12·5 (6·2–23·6)

Clinical diagnosis 7 12·6 (8·1–19·3)

Circumference 38 14·8 (11·4–19·0)

Perometry 17 16·4 (10·9–24·1)

Self-reported swelling 19 20·4 (13·8–29·0)

More than one measure 9 28·2 (11·8–53·5)

Time since breast cancer diagnosis or surgery*

3 to <6 months 8 10·3 (6·2–16·7)

6 to <12 months 15 13·8 (7·3–24·5)

12 to <24 months 24 18·9 (14·2–24·7)

2 to <5 years 30 18·6 (13·6–24·8)

≥5 years 16 15·6 (10·0–23·5)

More than one time category 6 7·6 (2·7–19·5)

ALND=axillary-lymph-node dissection. SLNB=sentinel-lymph-node biopsy. *Numbers (percentages) might not add to 72 (100%) because some studies measured lymphoedema with more than one method or at more than one timepoint.

Table 1: Incidence of breast cancer-related lymphoedema

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Sample size and characteristics

Measurement method Lymphoedema defi nition Incidence* Risk factors (RF)† Level of evidence‡ and study quality§

Prospective cohort studies

Armer et al (2010);5 USA

236 newly diagnosed patients followed up for 5 years

Arm circumferences; perometry

2 cm circumference; 200 mL perometry

At 6 months: 2 cm, 78/178 (44%)At 24 months: 2cm, 144/178 (81%);¶ 200 mL, 108/193 (56%)At 60 months: 2 cm, 167/178 (94%)

·· Level II

Bennett Britton et al (2007);29 UK

50 patients 12-months post-surgery and reassessed at 39–48 months

Arm volume >10% relative increase in volume of the ipsilateral arm

At 39–48 months: 14/50 (28%)¶

·· Level II

Bland et al (2003);30 USA

90 newly diagnosed patients (stage 0–IV) followed up for 3 years

Arm circumferences >2 cm change at any site At 3 years: 32/90 (36%)¶ ·· Level II

Celebioglu et al (2007);31 Sweden

60 newly diagnosed patients (grade 1–3) followed up for 3 years

Water displacement; lymphoscintigraphy

Arm volume: operated arm >10% the size of the non-operated armLymphatic dysfunction: clearance from the injection site, amount of indicator in the axilla vs in the injection site after 180 min, and time before 1% of the injected activity reached the axilla

Arm volume: 6/60 (10%)¶Lymphatic dysfunction: 3/60 (5%)

·· Level II

Clark et al (2005);24 UK


Percentage volume diff erence (PVD): diff erence in volume between the aff ected and unaff ected arm expressed as a percentage of the unaff ected limb volumePVD change: baseline to 3 years adjusted for volume change in the unaff ected limbClinical diagnosis

PVD change ≥5%Clinical diagnosis made by a health-care professional

PVD change ≥5% at 3 years: 19/188 (10%)¶Any LE at 3 years: 39/188 (21%)

·· Level II

Clough Gorr et al (2010);32 USA

400 newly diagnosed patients (stage I–III) followed up for 7 years

Self-reported swelling in the past 4 weeks

Persistent LE: positive response on at least two interviews over the follow-up period

Persistent LE (over 7 years): 145/400 (36%)¶

·· Level II

Devoogdt et al (2011);33 Belgium

49 patients (level I or II) 3-months post-surgery (axillary dissection) and followed up for 3·4 years

Arm circumference >10% diff erence between the involved and the uninvolved side; at least at one or both measurement sites

3 months: 2/49 (4%)3·4 years: 9/49 (18%)¶

·· Level II

Francis et al (2006);34 USA

155 newly diagnosed patients (stage 0–3) followed up for 12 months

Arm circumference and volume

Discrepancy in volume or circumference of ≥5%

12 months: total, 105/155 (68%); SLNB, 26/155 (17%); ALND, 73/155 (47%)

Severe LE (>10%): axillary surgery

Incidence: level IIRF: level IIStudy quality 10

Geller et al (2003);35 USA

145 initial interviews done an average of 9·7 months post-diagnosis and follow up interviews an average of 26 months; stage local or regional/distant recruited

Self-report arm swelling Arm or hand swelling since diagnosis

Follow-up: 55/145 (38%)¶ <50 years Incidence: level IIRF: level IIStudy quality 8

Goldberg et al (2010);36 USA

600 newly diagnosed patients, reassessed 3–8 years post-surgery (median of 5 years); node-negative recruited; T stage Tis to T2, N stage N0 to N1

Arm circumferences >2 cm for either the upper arm or the forearm

Follow-up: 31/600 (5%)¶ ·· Level II

Goldberg et al (2011);37 USA

600 newly diagnosed patients, reassessed 3–8 years post-surgery (median of 5 years); T stage Tis to T2, N stage N0 to N1

Self-reported swelling Current swelling Follow-up: 18/600 (3%) Greater number of lymph nodes removed during surgery


Han et al (2012);38 South Korea

97 newly diagnosed patients (N0–N3), reassessed every 3 months

Arm circumference ≥2 cm 6 months: total, 1/97 (1%);¶ SLNB, 0/14 (0%); ALND, 1/83 (1%)

·· Level II

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(Continued from previous page)

Hayes et al (2008a);39 Australia

287 patients (grade 1–3) recruited 6 months post-diagnosis when recruited

Bioimpedance spectroscopy 3 or more SDs higher than normative data

·· Age, income, surgery, physical activity levels

RF level IIStudy quality 12

Hayes et al (2008b);6 Australia

287 patients (grade 1–3) 6 months post-diagnosis and followed up for 18 months post-diagnosis

Cumulative burdenSOACBioimpedance spectroscopy (BIA)Self-reported arm swelling

SOAC measured by lymphoedema >5 cm; BIA measured by lymphoedema 3 or more SDs higher than normative data; self-reported arm swelling measured by lymphoedema defi nition of “yes”

6 months: SOAC (11%)9 months: SOAC (15%)12 months: SOAC (19%)15 months: SOAC (20%)18 months: SOAC (22%);¶ BIA (34%); self-report (45%)

Income, child status, side of treatment, lymph node excision, radiation, baseline symptoms


Hayes et al (2011);4 Australia

183 patients (grade 1–3) 6 months post-diagnosis and followed up to 6 years post-diagnosis

Bioimpedance spectroscopySelf-reported swelling

>3 SD above normHistory of arm swelling

6 year follow-up: BIA, 11/166 (7%); swelling, 40/183 (22%)

·· Level II

Helyer et al (2010);40 Canada

137 newly diagnosed patients (grade 1–3), followed-up for 20 months (1·6 years)

Arm volume >200 mL increase Arm volume at 20 months: 16/137 (12%)¶

BMI Incidence: level IIRF: level IIStudy quality 10

Herd-Smith et al (2001);41 Italy

1278 newly diagnosed patients (stage T1N0 to T4N+) and followed up for 4·6 years

Arm circumference Increase >5% 4·6 years post-diagnosis: 203/1278 (16%)¶

Radiotherapy; number of nodes removed


Kärki et al (2005);42 Finland

96 patients 6 months post-surgery and followed up for 12 months

SAQ impairments and severity Upper limb oedema 6 months: 23/96 (24%)12 months: 25/96 (26%)¶

·· Level II

Kosir et al (2001);43; USA

30 newly diagnosed patients (stage 0–3) followed up for 6 months

Arm volume ≥10% increase in limb volume 3 months: 1/20 (5%)6 months: 2/19 (11%)¶

·· Level II

McLaughlin et al (2008);44 USA

936 newly diagnosed patients (T stage Tis to T3; N stage N0 to N3) followed up for a median of 5 years post-surgery recruited

Arm circumferences and self-report swelling

>2 cmArm swelling

Circumferences: total, 86/936 (9%);¶ SLNB, 31/600 (5%); SLNB+ALND: 55/336 (16%)Current arm swelling: total, 109/936 (12%)

·· Level II

Norman et al (2009);25 USA

631 newly-diagnosed patients (stage in situ to III/IV) and followed up for 5 years

Self-reported presence and degree of LE

Whether right and left hands diff ered in sizeDiff erence rated: none (score 0), mild (1–3), moderate/severe (4–9)

Cumulative incidence: year 1, 160/631 (25%); year 2: 191/631 (30%);¶ year 3, 211/631 (33%); year 4, 228/631 (36%); year 5, 238/631 (38%)

·· Level II

Norman et al (2010);45 USA

631 newly diagnosed patients (stage in situ to III/IV) followed up for 5 years

Self-reported presence and degree of LE

Whether right and left hands diff ered in sizeDiff erence rated: none (score 0), mild (1–3), moderate/severe (4–9)

·· Any LE, BMI, education, ALND, any previous anthracycline-based chemotherapyModerate/severe, LE: ALNDChemotherapy

RF level IIStudy quality 9

Ozcinar et al (2012);46 Turkey

218 newly diagnosed patients (stage I, II, N0) followed up to 64 months post-surgery (5·3 years)

Arm circumference ≥2 cm 12 months: total 54/218 (25%),¶ SLNB 6/80 (8%), ALND 25/138 (18%); 64 months: total 16/218 (7%)

·· Incidence: level II

Pain et al (2005);47 UK

70 newly diagnosed patients followed up for 12 months

Volume ≥10% relative increase in volume of all or part (forearm or upper arm) of the ipsilateral arm

3 months: 11/70 (16%)12 months: 8/70 (11%)¶

·· Level II

Paskett et al (2007);48 USA

622 newly diagnosed patients (stage I–III) followed up for 3 years

SAQ: arm and hand swelling Any swelling in their arm or hand since surgery or in the past 6 months

By 1 year: 224/622 (36%)By 3 years: 336/622 (54%)¶

Persistent swelling, number of nodes removed, obese


Petrek et al (2001);49 USA


Self-reported arm circumferences: standardised mailed instrument, verbal reports of arm swelling during telephone interviews

No LE: no arm swelling plus diff erence of ≤1·27 cmMild: <1·27 cm plus self-report of arm enlargement or heavinessModerate: >1·27 cmSevere: ≥5·08 cm

During the 20 years follow-up LE was identifi ed in: 128/263 (49%)¶

·· Level II


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Quinlan et al (2009);50 Canada

278 patients (stage I–III) 6–12 months post-surgery

Arm morbidity: volume, McGill Pain SAQRange of motion

Any of the following: >10% increase, score >0, <80° for rotation, <170° for abduction

Some form of arm morbidity: 211/278 (76%)

·· Level II

Rampaul et al (2003);51 UK

1242 patients diagnosed between 1973 and 2000 and assessed at various times of follow-up

Self-reported arm swelling within a 15 week period at the clinic

Problematic arm symptoms Arm swelling: 5/1242 (<0·5%)¶

·· Level II

Ronka et al (2005);52 Finland

83 newly-diagnosed patients (stage Tis to T4) and followed up for 12 months

Arm circumference, self-reported arm oedema

Mean diff erence at the six measurement points (LE%) >5%, arm oedema

1 year post-surgery: circumference: 13/83 (16%);¶ self-report, 35/83 (42%)

·· Level II

Schrenk et al (2000);53 Austria

70 newly diagnosed patients (T stage T1a to T2) with a median follow-up of 15·4 months in the SNLB group and 17 months in the ALND group

Self-report (none, mild, moderate, severe)

Arm swelling of the operated arm compared with the non-operated arm (mild: periods of arm swelling but no constant increase in greatest dimension and clothes fi t the same, to severe: constant arm heaviness, disability, decreased functional activity, huge arm swelling)

At follow-up: total, 19/70 (27%);¶ SLNB, 0/35 (0%), ALND 19/35 (54%)

·· Level II

Stout Gergich et al (2008);54 USA

196 newly diagnosed patients (stage 0–3) followed-up for 18 months

Perometer Volume increase ≥3% in treated upper limb compared with pre-operation measure

Cumulative: 43/191 (23%) ·· Level II

Wilke et al (2006);55 USA

5327 newly diagnosed patients (stage T1 to T2) followed up for 6 months

Arm circumference >2 cm change from baseline compared with contralateral arm

6 months: 201/2904 (7%)¶ Age, BMI Incidence: level IIRF: level IIStudy quality 10

Wojcinski et al (2012);56 Germany

34 newly diagnosed patients (who had ALND surgery) followed-up for 6 months

Arm circumference or subjective complaints or medical treatment

≥4 cm, manual compression lymphatic massage, compression garments, bandaging

3 months: 12/34 (35%)6 months: 16/34 (47%)¶

·· Level II

Yang et al (2010);57 South Korea

191 newly diagnosed patients followed up for 12 months

Arm circumference >1 cm diff erence 3 months: 11/191 (6%)6 months: 16/187 (9%)12 months: 22/183 (12%)¶

LE at 12 months: ALND


Retrospective cohort studies

Crosby et al (2012);58 USA

1117 patients (1499 breasts) 56 months post-treatment

Subjective or objective Data documented by health-care providers

50/1499 (3%)¶ Axillary interventions, greater number of positive lymph nodes, radiation therapy, BMI

Incidence: level III-3RF: Level III-2Study quality 9

Hayes et al (2008c);59 USA

2579 patients (stage I–II)81 months post-treatment

Assessed at regular intervals (every 6–12 months after radiotherapy) by the treating radiation oncologist

Severity: graded by the physician’s physical examination

464/2579 (18%) Radiotherapy fi eld, obesity index, adjuvant therapy, number of lymph nodes dissected

Incidence: level III-3RF: level III-2Study quality 9

Hinrichs et al (2004);60 USA

105 patients (stage I–IV) post-radiotherapy

Oedema Presence of ipsilateral arm oedema noted by a treating physician (severity based on the treating physician’s impression)

Median time to onset 391 days (range, 33–1632 days): 28/105 (27%)¶

Radiotherapy before 1999


Kingsmore et al (2005);61 UK

2122 patients (grade 1–3), median follow-up of 8 years since diagnosis

Objective persistent arm swelling noted by clinician

At least 1 year after completion of axillary treatment requiring further treatment—eg, a compression sleeve

Total, 136/1960 (7%);¶ SLNB, 20/146 (5%); ALND, 69/1099 (6%)

·· Level III-3

Lumachi et al (2009);62 Italy

205 patients (pT1b to pT2) with median follow-up of 22 months post-surgery

Arm circumferences >2 cm Total, 15/205 (7%);¶ SLNB, 2/54 (4%); ALND, 13/151 (9%)

·· Level III-3

Mathew et al (2006);63 UK

506 patient >2 years post-surgery

Arm circumferences >2 cm Total, 31/506 (6%);¶ SLNB, 7/312 (14%); ALND, 24/194 (12%)

·· Level III-3

Powell et al (2003);64 USA

727 newly diagnosed patients (stage I–II) given breast conservation treatment included

Arm circumferences assessed at regular intervals

> 2cmPersistent oedema: if symptoms did not resolve at subsequent visits

Persistent arm lymphoedema, 21/727 (3%)¶

·· Level III-3


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Schijven et al (2003);65 Netherlands

393 patients (stage 0–III)3 months to 3 years post-treatment

SAQ: treatment-specifi c QoL SAQ developed and validated for this study

Complaint present if responded 2–3; absent if responded 0–1

Total, 17/393 (4%);¶ SLNB, 2/180 (1%); ALND, 15/213 (7%)

ALND Incidence: Level III-3RF: III-2Study quality 9

Shih et al (2009);66 USA

1877 patients; used data for the 2 years after treatment

Insurance claims for LE treatment or diagnosis on health insurance database

Formal diagnosis listed on health insurance claims database

Within 2 years of treatment initiation, 180/1877 (10%);¶ 4 year follow-up, 12%

ALND; chemotherapy


Wernicke et al (2011);67 USA

265 patients (stage T1 to T2) median follow-up at 9·9 years post-treatment

Arm circumferences >1 cm diff erence Total, 45/223 (20%);¶ SLNB, 5/108 (5%); SLNB+ALND, 40/115 (35%)

·· Level III-3

Randomised clinical trials

Ahmed et al (2006);68 USA

45 patients (stage DCIS to III), 23 in intervention (weight training) and 22 in control; 22 months post-diagnosis at baseline

Arm circumference, self-reported clinician diagnosis

Circumference ≥2 cm; self-reported clinical diagnosis of LE at baseline

Baseline results for total sample: 2 cm, 8/45 (18%);¶ clinical diagnosis, 13/45 (29%)Control group at 6 months follow-up (post-intervention): 2 cm, 1/22 (5%)

·· Level IV

Box et al (2002);69 Australia

65 newly diagnosed patients (stage I–III), 32 in treatment (early physiotherapy after axillary dissection), 33 in control

Arm circumferences (CIRC); arm volume; multi-frequency bBioimpedance impedance (MFBIA)

Increase ≥ 5cm from pre-operation, increase ≥200 mL from pre-operation operated arm:unoperated arm ratio ratio below the 95% CI of pre-operation study group

Results for control group3 months: 5 cm, 0/33 (0%)6 months, 5 cm: 1/33 (3%)12 months: 5 cm: 1/33 (3%)24 months: 5 cm: 4/33 (12%);¶ 200 mL, 9/33 (27%); MFBIA, 5/33 (15%)

BMI Incidence: level III-2RF: level IVStudy quality 13

Lee et al (2007);70 Australia

61 patients (stage DCIS to III), 30 in the control group and 31 in the intervention group (stretching after radiotherapy); 3·4–3·7 months post-surgery

Arm circumference >2 cm Results for control group3 months: 6/61 (10%)7 months: 4/30 (13%)¶

·· Level III-2

Lucci et al (2007);71 USA

891 newly diagnosed patients (T stage T1 or T2 recruited; N0, M0)445 SLND+ALND (usual), 446 SLND aloneNewly-diagnosed

Arm circumferences; subjective (risk factors)

>2 cm; patient self-report or physician diagnosis (risk factors)

6 months: total, 50/541 (9%)12 months: total, 40/468 (9%)¶SLND alone: 14/226 (6%)SLNB+ALND: 26/242 (11%)

ALND; age Incidence: level III-2RF: level IIStudy quality 9

Mansel et al (2006);72 UK

1031 newly diagnosed patients (stage I–III); 515 SLNB, 516 standard axillary surgery

Self-assessment for severity Mild, moderate, severe 3 months: total, 81/812 (10%)6 months: total, 90/846 (11%)12 months: total: 73/815 (9%);¶ SLNB, 20/412 (5%), ALND, 53/403 (13%)

ALND Incidence: level III-2RF: level IIStudy quality 10

Schmitz et al (2010);73 USA

154 patients (stage in situ to III), 77 in intervention (weight lifting) and 77 control; 1–5 years post-diagnosis at study entry

Arm volume; clinician-defi ned ≥5%; certifi ed LE therapists used a standardised clinical assessment, including inter-limb diff erences, changes in tissue tone or texture, and symptoms

Results for control group at 1 year (post-intervention)Arm volume, 13/75 (17%);¶ clinician-defi ned, 3/69 (4%)

·· Level III-2

Veronesi et al (2003);74 Italy

516 patients (grade 1–3): 257 in the axillary-dissection group (SLNB+total axillary dissection) and 259 in the sentinel-node group (SLNB+axillary dissection if SLNB contained metastases); 100 patients in each study group was used to describe side-eff ects6 and 24 months after surgery

Arm circumference >2 cm 6 months: total, 8/200 (4%)24 months: total, 12/200 (6%);¶ SLNB, 0/100; ALND, 12/100 (12%)

·· Level IV

Case–control studies

Soran et al (2006);75 USA

156 patients (T stage 0 to IV): 52 with LE, 104 without (control)Breast/axillary surgery between 1990 and 2000

Arm circumferences: severity defi ned according to diff erence in volume between aff ected and unaff ected arms

Still well: % above normal arm: slight, 11–20; moderate, 21–40; marked, 41–80; severe, >80

·· Infection of the operated sideHigh body-mass index, more use of hand (occupation/hobby)

RF level III-3Study quality 6


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Swenson et al (2009);76 USA

388 patients: 94 with LE, 94 without (control)Average of 6 years after surgery

Clinical diagnosis; referred for LE management; arm circumferences

·· ·· Overweight RF level III-3Study quality 6

Cross-sectional studies

Ahmed et al (2008);77 USA

1287 (stage in situ to regional or distant); 8·1 years post-diagnosis

Self-reported LE Self-reported diagnosis 104/1287 (8%)¶ ·· Level IV

Armer et al (2004);78 USA

100 patients (stage 0 to IV)28 months post-surgery

Arm circumferences ≥2 cm Total: 36/100 (36%)¶SLNB alone: 2/9 (22%)ALND+SLNB: 32/79 (41%)

·· Level IV

Asim et al (2012);79 New Zealand

193 who had ALND, 56 months post-surgery

Arm circumference; arm volume; self-reported arm swelling

≥2 cm; ≥10%; quite a bit or very much

≥2 cm: 49/193 (25%)¶>10%: 14/73 (19%)Swelling: 21/193 (11%)

Increasing age; radiotherapy to axilla; radiotherapy to breastInfection to operated arm

Incidence: level IVRF: level IVStudy quality 7

Blanchard et al (2003);80 USA

776 patients with early-stage invasive node-negative breast cancer (stage 0 to III); 2·4 years post-surgery

Self-reported presence of arm LE

·· Total: 70/774 (9%)¶SLNB-only: 39/683 (6%)SLNB+ALND: 31/91 (34%)

·· Level IV

Deo et al (2004);81 India

299 patients (stage I–III)2·5 years post-treatment

Arm circumferences >3 cm 100/299 (33%)¶ Axillary irradiation; comorbidities


Edwards et al (2000);82 Australia

201 patients 3 years post-treatment

Water displacement; subjective assessment

≥10% diff erence between limbs; swelling

Objective: 22/201 (11%)¶Subjective: 48/201 (24%)

·· Level IV

Eversley et al (2005);83 USA

116 patients (stage I–IV) diagnosed and treated in the past 2 years

Swelling from LE (1–10 scale) LE related swelling 73/116 (63%)¶ ·· Level IV

Freitas-Silva et al (2010);84 Brazil

70 patients (stage I–III)2·5–3·5 years post-surgery

Arm circumferences ≥2 cm diff erence between limbs Overall prevalence of LE: 11/70 (16%)¶

·· Level IV

Golshan et al (2003);85 USA

125 patients (TNM stage 1 to 3) >1 year post-surgery

Arm circumferences >3 cm diff erence between operated and non-operated side

Total: 15/125 (12%)¶SLNB: 2/77 (3%)ALND: 13/48 (27%)

·· Level IV

Graham et al (2006);86 Australia

91 patients (T stage 1–4)4·2 years post-radiotherapy

Arm circumferences; limb volume

Arm circumferance: >2 cm; volume >200 mL

Circumferance: 40/89 (45%);¶ volume 36/85 (42%)

LE by VOL+CIR: axillary irridationAge


Haddad et al (2010);87 Iran

355 patients, 79–84 months post-surgery

Arm circumferences Increase of 10% in the circumference of the arm on the involved side compared with the opposite arm

62/355 (17%) ·· Level IV

Hayes et al (2005);88 Australia

176 Patients (grade 1–3) 6 months post-diagnosis

Arm circumferences; sum of arm circumferences; multifrequency bioimpedance spectroscopy; self-reported arm swelling

SOAC: >5 cmSOAC: >10%MFBIA: ≥3 SDSelf-report: yes in previous 6 months

·· Side of treatment; blood pressure readings taken on operated arm

RF level IVStudy quality 10

Kwan et al (2002);89 Canada

467 patients , >2 years post-diagnosis

Arm volume ≥200 mL 14/112 (13%)¶ ·· Level IV

Leidenius et al (2005);90

Finland

139 patients 3 years post-surgery

Arm circumferences; clinical signs; self-report

>2 cm between operated and non-operated wrist; swelling

>2 cm: 3/139 (2%)¶Clinical signs: 7/139 (5%)Swelling: 18/139 (13%)

·· Level IV

Lopez Penha et al (2011);91 Netherlands

145 patients, >5 years post-surgery

Arm circumferences; perometry; self-report

>5 cm>200 mLSwelling in the past year of the upper-limb on the treated side

5 cm: 23/145 (16%)¶SLNB: 24/76 (32%)ALND: 37/69 (54%)Total: 200mL, 11/145 (8%); self-report, 25/145 (17%)

·· Level IV


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diagnosis of lymphoedema was 12·6%, whereas the incidence by all other methods of assess ment was between 14·8% (circumferences) and 20·4% (self-reported swelling; table 1). The incidence of arm lymphoedema seemed to increase with time up to 2 years from diagnosis or surgery, after which incidence seemed

to decrease (table 1); incidence in women who had axillary-lymph-node dissection was almost four times higher than it was in those who had sentinel-lymph-node biopsy (table 1, fi gure 2).

Of the 29 studies (involving 17 933 participants) that investigated risk factors, two were low quality, 17 were of




McCredie et al (2001);92 Australia

809 patients, median of 3·1 years post-diagnosis

Self-reported arm problems: shoulder stiff ness, arm swelling, arm numbness or pain or ache in the arm

Arm problem on the treated side (excluding the fi rst 6 months after diagnosis)

Arm swelling: 1–1·9 years post-diagnosis, 20%; 2–2·9 years post-diagnosis, 25%;¶ 3–3·9 years post-diagnosis, 28%; ≥4 years post-diagnosis, 29%

Arm swelling; BMI Incidence: level IVRF: level IVStudy quality 8

Meeske et al (2009);93 USA

494 (stage in situ to III-A) <18 months post-diagnosis to 4 years post-diagnosis

Self-reported arm LE Swelling due to an accumulation of fl uid in their arm, not to be confused with swelling that occurs after surgery

4 years post-diagnosis120/494 (24%)¶

Age at diagnosis; high blood pressure; BMI>10 nodes excised


Nagel et al (2003);94 Netherlands

106 (stage I–III); median of 14·3 months post-surgery

Arm circumferences; volume ≥2 cm; >200 mL Circumference: 10/106 (9%)Volume: 13/106 (12%)

·· Level IV

Nesvold et al (2008);95 Norway

263Median of 47 months post-surgery; stage II recruited

Volume+circumferencesSelf-report

≥10% in volume or ≥2cm circumferenceArm swelling

Volume/arm circumference: 43/263 (16%)¶Swelling: 63/263 (24%)

Number of metastatic axillary lymph nodes; redical modifi ed mastectomy; BMI


Ozaslan et al (2004);96 Turkey

240 patients (stage I–III)18–43 months post-surgery

Arm circumferences >4 cm 22/240 (9%)¶ Axillary radiotherapy; BMI


Paim et al (2008);97 Brazil

96 patients, 6–60 months post-surgery

Perimetry. Symptoms: heaviness, swelling, tightness, fi rmness

≥1 cm, plus ≥2 symptoms Total: 16/96 (17%)¶SLNB: 2/48 (4%)ALND: 14/48 (29%)

·· Level IV

Park et al (2008);98 South Korea

450 patients (stage I–III)12–24 months post-surgery

Arm circumferences ≥2 cm 112/450 (25%) Stage; modifi ed radical mastectomy; axillary dissection; axillary radiotherapy; BMI; low exercise; low LE education; low preventive; self-care activities


Querci della Rovere et al (2003);99 UK

201 patients (grade 1–3)>6 months post-treatment

Arm circumferences; subjective

>2 cm; >5% any site (risk factors); swelling noted by patient with clinical inspection by nurse or doctor

>2 cm: 44/198 (22%)¶Subjective: 20/199 (10%)

Dominant side; positive nodal status; chemotherapy


Thomas-MacLean et al (2008);100 Canada

347 patients (stage I–III)6–12 months post-diagnosis

Arm circumferences; volume >2 cm diff erence; >150 mL diff erence

>2 cm: 39/347 (11%)¶>150 mL: 31/347 (9%)

·· Level IV

van der Veen et al (2004);101 Belgium

245 patients, time not specifi ed

Arm circumferences ≥2·5 cm diff erence 59/245 (24%) ·· Level IV

Velloso et al (2011);102 Brazil

45 patients, 21·3 months post-surgery

Arm circumferences >10% diff erence 2/45 (4%)¶ ·· Level IV

Incidence data are n/N (%). ALND=axillary lymph node dissection. LE=lymphoedema. SLNB: sentinel-lymph-node biopsy. SOAC=sum of arm circumferences. SAQ: self-administered questionnaire. Tis=carcinoma in situ. QoL=quality of life. BMI=body-mass index. *Timing of incidence reported is the timing lymphoedema was measured relative to diagnosis of breast cancer. †Risk factors shown to be statistically signifi cant (p≤0·05) in multivariable analyses or randomised clinical trials. ‡Level of evidence (as per National Health and Medical Research Council guidelines): incidence level is the level of evidence for incidence component; RF level is the level of evidence for risk factor component. §Study quality: each item of a selected study, which met our criteria, was assigned one point (the highest possible score was 14—the higher the score the higher the study quality). ¶Data selected as per the hierarchy of decisions and which are used in the meta-analysis pooled estimate.

Table 2: Studies reporting lymphoedema incidence or prevalence after breast cancer treatment and associated risk factors

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moderate quality, and ten were high quality (table 3). Risk factors that are lent support by a strong level of evidence (consistent fi ndings in at least 75% of studies, including at least two high-quality studies) include receipt of axillary-lymph-node dissection, and having a mastectomy, a greater number of lymph nodes dissected, and a high body-mass index. Risk factors that are lent support by a moderate level of evidence (consistent fi ndings in at least 75% of studies, including at least one high-quality study) are the presence of metastatic lymph nodes, receipt of chemotherapy or radiotherapy, and not participating in regular physical activity. We identifi ed weak or inconclusive evidence to lend support to other risk factors: demographic characteristics (children,

income, age, education), disease (axillary radiotherapy, stage, postoperative infection), side of treatment, and lifestyle-associated factors (blood pressure, preventive self-care activities, upper body symptoms, comorbidities, hand use, education about lymphoedema).

DiscussionOur fi ndings suggest that of the 1·38 million women worldwide diagnosed with breast cancer every year,103 295 320 (21%) will develop arm lymphoedema. These fi ndings are based on data from prospective cohort studies, which are well suited for assessing incidence. Although similar to reports from previous reviews,2,7,104 which averaged the incidence results from included studies, the subgroup analyses reported here provide additional insight. First, the incidence of arm lymphoedema seems to increase over time, at least up to 24 months after breast cancer diagnosis or surgery, although two prospective cohort studies25,48 have shown that cases continue to accumulate beyond this period but at a slower rate. Second, whereas almost one in fi ve women with breast cancer living in North America, Australasia, Asia, and the Middle East develop secondary lymphoedema, less than one in six women in Europe, the UK, and South America develop the disorder. Third, this high rate of arm lymphoedema is about four times more likely when axillary-lymph-node dissection is used compared with when the more conservative sentinel-lymph-node biopsy procedure is used. Finally, substantial evidence lends support to several risk factors for arm lymphoedema, including extensive surgery, a high body-mass index, adjuvant therapy, and low physical activity—these factors are potential targets for future prevention strategies or for more eff ective management of the disorder.

The accuracy of our estimate of arm lymphoedema incidence (21·4%) should be considered. Missing data can aff ect estimates of incidence. However, the direction of the bias is unknown because we do not know whether individuals who develop lymphoedema would be more or less likely to remain in a study (eg, they might be more likely to remain in a study because their lymphoedema is being measured, or they might be less likely to remain in the trial, because those who are more ill tend to drop out of research studies). By contrast with prospective cohort studies, retrospective studies rely on data recall or information available from records collected for other purposes, cross-sectional studies often show the prevalence of lymphoedema only at one timepoint or include women at a wide range of times after treatment, and clinical trials might recruit and follow-up study populations with inherent bias (eg, restrictive eligibility criteria or low recruitment rates decrease the likelihood of participants being represen tative of the wider population of patients). All these limitations would tend to yield lower lymphoedema incidence, as we saw in this study (table 1). Furthermore, the incidence of arm lymphoedema is likely to be underestimated irrespective

Figure 2: Incidence of arm lymphoedema after sentinel-lymph-node biopsy (A) and axillary-lymph-node dissection (B)

Armer et al (2004)78 9 0·222 (0·056–0·579)Blanchard et al (2003)80 683 0·057 (0·042–0·077)Francis et al (2006)34 155 0·168 (0·117–0·235)Golshan et al (2003)85 77 0·026 (0·007–0·098)Han et al (2012)38 14 0·033 (0·002–0·366)Kingsmore et al (2005)61 416 0·048 (0·031–0·073)Lopez Penha et al (2011)91 76 0·316 (0·222–0·428)Lucci et al (2007)71 226 0·062 (0·037–0·102)Lumachi et al (2009)62 54 0·037 (0·009–0·136)Mansel et al (2006)72 412 0·049 (0·032–0·074)Mathew et al (2006)63 312 0·022 (0·011–0·046)McLaughlin et al (2008)44 600 0·052 (0·037–0·073)Ozcinar et al (2012)46 80 0·075 (0·034–0·157)Paim et al (2008)97 48 0·042 (0·010–0·152)Schijven et al (2003)65 180 0·011 (0·003–0·043)Schrenk et al (2000)53 35 0·014 (0·001–0·187)Veronesi et al (2003)74 100 0·005 (0·000–0·074)Wernicke et al (2011)67 108 0·046 (0·019–0·106)Total 0·056 (0·037–0·085)

Armer et al (2004)78 79 0·405 (0·303–0·516)Blanchard et al (2003)80 91 0·341 (0·251–0·444)Francis et al (2006)34 155 0·471 (0·394–0·550)Golshan et al (2003)85 48 0·271 (0·164–0·412)Han et al (2012)38 83 0·012 (0·002–0·081)Kingsmore et al (2005)61 1099 0·063 (0·050–0·079)Lopez Penha et al (2011)91 69 0·536 (0·419–0·650)Lucci et al (2007)71 242 0·107 (0·074–0·153)Lumachi et al (2009)62 151 0·086 (0·051–0·143)Mansel et al (2006)72 403 0·132 (0·102–0·168)Mathew et al (2006)63 194 0·124 (0·084–0·178)McLaughlin et al (2008)44 336 0·164 (0·128–0·207)Ozcinar et al (2012)46 138 0·181 (0·125–0·254)Paim et al (2008)97 48 0·292 (0·181–0·434)Schijven et al (2003)65 213 0·070 (0·043–0·114)Schrenk et al (2000)53 35 0·543 (0·379–0·698)Veronesi et al (2003)74 100 0·120 (0·069–0·200)Wernicke et al (2011)67 115 0·348 (0·267–0·439)Total 0·199 (0·135–0·282)

N umber of studies Event rate (95% CI) A

B

1·00–0·5 0·5–1·0

Decreased incidence Increased incidence

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of study design. Lymph oedema is acute for some patients, fl uctuating or chronic for others, with the potential for new cases to present beyond 2 years post-diagnosis.25,39 Therefore, prevalence data, especially when frequency of assessment or length of follow-up are restricted, are unlikely to capture all cases.

The type of method used to diagnose lymphoedema also aff ects incidence data (table 1). Because each method assesses diff erent attributes of lymphoedema,2 its diag-nostic sensitivity will depend on the lymphoedema characteristics of the cohort being measured, with the use of multiple methods of assessment leading to higher incidence (28% compared with ≤20% for all other individual methods; table 1). Incidence derived from only one method of assessment, none of which took into account the possibility of breast or trunk lymphoedema,

was included in the meta-analysis. Finally, characteristics of the cohort assessed in the prospective cohort studies also aff ect incidence data. Treatment advances—some being associated with reduced lymphoedema risk (eg, sentinel-node biopsy) and others being associated with increased risk (eg, chemotherapy)—diff er between and within countries (eg, regional vs urban areas; racial disparities in treatment). Also, stage of disease or other demographic characteristics (eg, level of health insurance, access to health care) will dictate the need for more invasive surgery and adjuvant therapy, irrespective of subsequent risk of lymphoedema. Nearly half (13 of 30 studies) of the prospective cohort studies included in the meta-analysis involved North American women, and seven of these studies discussed the representativeness of their sample; only two regarded their sample as

Strong evidence Moderate evidence Weak evidence Inconclusive evidence

Demographics

Children in care aged ≤14 years* ·· ·· 1 (OR 0·2) ··

High income* ·· ·· 2 (OR 0·2–0·5) ··

Age†‡ ·· ·· ·· 7 (OR 0·4–3·3)

Education* ·· ·· ·· 1 (HR 1·5)

Disease and treatment

Axillary lymph node dissection†§ 9 (OR 1·3–6·7; RR 2·7; HR 2·5–2·6) ·· ·· ··

Greater number of lymph nodes dissected†

6 (OR 1·0–2·1; HR 1·2) ·· ·· ··

Mastectomy† 3 (OR 2·7–7·4) ·· ·· ··

Higher number of metastatic lymph nodes*

·· 3 (OR 1·1–2·8: RR 2·0) ·· ··

Radiotherapy† ·· 5 (OR 1·7–3·8; HR 1·3) ·· ··

Receiving chemotherapy* ·· 5 (OR 1·6–2·0; HR 1·4–3·7) ·· ··

Axillary radiotherapy ·· ·· 5 (OR 0·1–7·7; HR 0·1; RR 2·7) ··

Higher stage of disease ·· ·· ·· 1 (OR 2·5)

Postoperative infection ·· ·· ·· 2 (OR 6·7–32·5)

Treatment on the dominant side* ·· ·· ·· 4 (OR 0·2–4·7; RR 2·9)

Lifestyle and behaviours

Higher body-mass index†‡ 14 (OR 0·1–5·5; HR 1·4; RR 5·5) ·· ·· ··

Did not participate in regular physical activity*

·· 2 (OR 2·1–6·1) ·· ··

Had blood pressure readings taken on the treated side*

·· ·· 1 (OR 3·4) ··

Had not done preventive self-care activities

·· ·· 1 (OR 12·4) ··

Presence of at least mild upper-body symptoms*

·· ·· 1 (OR 2·3–3·1) ··

Presence of comorbidities* ·· ·· 2 (OR 1·6; HR 0·1) ··

High blood pressure before breast cancer

·· ·· ·· 1 (OR 2·3)

Occupation requiring a high level of hand use (eg, computer programmer)

·· ·· ·· 1 (OR 2·1–4·6)

Not receiving pretreatment education of lymphoedema

·· ·· ·· 1 (OR 2·2)

Data are number of articles (range of summary statistics). HR=hazard ratio. OR=odds ratio. RR=relative risk. *Evidence includes one level two (prospective cohort) study. †Evidence includes at least two level two (prospective cohort) studies. ‡Evidence includes one randomised clinical trial. §Evidence includes at least two randomised clinical trials.

Table 3: Summary of possible risk factors from multivariable analyses for the development of breast cancer-related lymphoedema

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representative of the wider breast cancer population (in terms of disease and treatment characteristics). Women living in more rural and regional areas and women of specifi c ethnic origins (eg, black women) are under-represented in the data included in this meta-analysis. A combination of the above issues could have aff ected the incidence estimate for each country (table 1). Overall, we consider our fi nding that 21·4% of women will develop arm lymphoedema after breast cancer to be a conservative estimate.

The call to integrate prospective surveillance of lymph-oedema into standard breast-cancer care is building momentum,105–107 in part because early detection of lymphoedema is believed to have been associated with more eff ective treatment and prevention of progression. Unfortunately, little scientifi c evidence exists to lend support to this idea. Although a prospective cohort study has shown that treating lymphoedema with compression led to its successful resolution, the effi cacy of com-pression was not compared with a control group.54 Also, fi ndings from several prospective cohort studies show that lymphoedema, at least during the fi rst 18–24 months after breast cancer, might dissipate with or without treatment in some patients.5,25,39 These results draw attention to the risk of giving unnecessary lymphoedema treatment, which would come at individual and public health cost. Nonetheless, the physical, psychosocial, and fi nancial burden associated with lymphoedema is well established,66,108 lymphoedema is more likely to be under-diagnosed than over-diagnosed (with the exception of lymphoscintigraphy incidence, incidence was lowest when reliant on a clinical diagnosis; table 1), and it is likely that with more research, early detection, and management of the disorder will prove cost-eff ective.109 Therefore, fi ndings from this meta-analysis could be used to guide the methods (ie, measurement technique, defi nition of lymphoedema, timing of assessments) of prospective surveillance of lymphoedema in clinical practice, to optimise early diagnosis, and to minimise the potential for overtreatment.

Because most patients seem to present within the fi rst 2 years after breast cancer, more frequent surveillance throughout this time (eg, once every 3–6 months) seems reasonable. The sensitivity of diagnostic methods could be considered when deciding which method to use and when. Bioimpedance spectroscopy has been shown to be sensitive to early extracellular fl uid changes, is fast, reliable, and easy to administer,27 with testing being reimbursed by some private health insurers in the USA.109 The circumferences method is inexpensive (little equipment needed, although it requires staff time), reliable when used by trained assessors, and might be the most appropriate method in the long term because it detects size change and inter-limb size diff erences irrespective of the tissue composition of the lymph-oedema. However, it has little sensitivity to detect preclinical lymphoedema and needs to take into account

bodyweight changes over time by assessing relative change or inter-limb diff erences rather than absolute scores.2 Self-report methods are also inexpensive, and, unlike objective methods, can capture other symptoms alongside arm symptoms potentially indicate lymph-oedema over an extended period of time. However, used on their own, self-report methods lack specifi city, because many symptoms associated with lymphoedema are also common after breast cancer in women without lymphoedema.11

In view of the pros and cons of the various methods, it seems more reasonable to expect the use of multiple methods over the use of any one method as being the gold standard in the diagnosis of lymphoedema. However, use of multiple measures might not be feasible in the clinical setting. Instead, clinics could rely on specifi c methods during specifi c periods. For example, bioimpedance spectroscopy could be used during the fi rst 6–12 months, followed by circumferences up to 2 years after treatment. When there is evidence of lymphoedema, additional methods could then be used to assist in a defi nitive diagnosis. Alternatively, a second measure could be scheduled (outside the standard prospective surveillance protocol), and only when lymphoedema is confi rmed at this additional visit (or shows signs of further progression later), is treatment initiated. The potential advantages of being able to change the methods during the prospective surveillance period, for assessment or confi rmation of a diagnosis, would be best realised when multiple methods are used to document patients’ status before treatment. However, even in this ideal situation, pretreatment assessment might not accurately show baseline lymph oedema status; swelling can present before treatment and the contribution of the breast cancer disease to lymphoedema remains unknown.

One potential way to optimise the cost-eff ectiveness of prospective surveillance is to stratify women into a more or less frequent and comprehensive surveillance protocol based on presence of lymphoedema risk factors. Unfortunately, due to insuffi cient raw data being re-ported in the included risk factor studies, we were unable to report a common statistic (notably risk ratios) for each of the potential risk factors. Although the absence of risk ratios is a limitation of this work, our fi ndings nonetheless clearly indicate that there is strong evidence showing that more extensive surgery (chest wall and axilla) and being overweight or obese are associated with increased risk of lymphoedema, and moderate evidence that also lends support to adjuvant therapy (radiation and chemotherapy) and sedentary lifestyles as risk factors. Our detection of chemotherapy as a risk factor is in contrast with the fi ndings of a previous meta-analysis on breast cancer-related treat ment risk factors.10 A possible reason that we detected chemotherapy as a risk factor is because it is a surrogate measure for more advanced disease and thus more extensive surgical treatment, or it might be indicative of an adverse interaction between

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more chemotherapeutic agents available in the past decade and the lymph system. The detection of sedentary lifestyle as a risk factor is, to our knowledge, a new fi nding and could be as a consequence of a major lymph fl ow mechanism (the muscle pump) being inactive.

There are several factors to be considered before our risk-factor fi ndings are used for risk-stratifi cation purposes. First, these risk factors alone do not accurately predict who will develop arm lymphoedema and who will not. These specifi c factors represent six of 12 iden tifi ed risk factors in one, prospective, population-based cohort study, which together explained only 35% of variation between those who did and those who did not develop lymphoedema.39 Furthermore, women can and do present with arm lymphoedema despite having healthy bodyweight, regular physical activity levels, and lumpectomy surgery. Finally, little is known about the potential contribution of the cancer itself, or the possible importance of genetic predisposition, to lymphoedema risk. Findings from animal models110 and one study in human beings111 provide preliminary evidence for a contribution of genetic susceptibility to the development of secondary lympho edema after breast cancer. None-theless, current under standing of risk factors can inform lymphoedema prevention and management strategies. Although treatment-related risk factors are largely not modifi able (because they are generally dictated by the type and stage of disease and available treatment options), substantial scope exists for the modifi cation of patients’ physical activity levels and bodyweight after breast cancer: most women with breast cancer are insuffi ciently active at diagnosis112–114 and more than 50% are overweight or obese.115

Further research is needed to improve our under-standing of risk factors (including further exploration of known risk factors, such as whether lymphedoema rates diff er between those with delayed axillary-lymph-node dissection after sentinel-node biopsy compared with axillary-lymph-node dissection from the outset), as well as prevention and treatment strategies. Only with increased knowledge will we be in a position to improve further the lives of women with breast cancer, and reduce the overall socioeconomic burden of this disabling, distressing disorder.

ContributorsTD, BN, and SH participated in the conception and design of the review.

TD and SR participated in the extraction and analysis of data. TD, SR,

BN, and SH participated in the interpretation of data and writing of the

paper. All authors approved the fi nal version.

Confl icts of interestWe declare that we have no confl icts of interest.

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incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis

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