Clinical and technical evidence

Advice

Published evidence
Overall assessment of the evidence
Recent and ongoing studies

Clinical and technical evidence

A literature search was done for this briefing in accordance with the interim process and methods statement. This briefing includes the most relevant or best available published evidence relating to the clinical effectiveness of the technology. Further information about how the evidence for this briefing was selected is available on request by contacting mibs@nice.org.uk.

Published evidence

Three studies are summarised in this briefing. These are a prospective observational study (Barrio et al. 2015) done in the US with 186 patients; a prospective observational study done in the UK with 612 patients (Bundred et al. 2015); and a prospective observational study done in the US with 180 patients (Soran et al. 2014).

Overall assessment of the evidence

There are few available studies comparing the diagnostic accuracy of the L‑Dex U400 to other ways of diagnosing lymphoedema. There are no published randomised controlled studies to help further inform the clinical utility of the L Dex U400.

The 2 large comparative studies (Barrio et al. 2015; Bundred et al. 2015 suggest that the L‑Dex U400 has a lower diagnostic accuracy than volume displacement and perometry, respectively. However, it should be noted that in these studies, the comparators were assumed by the authors to be the gold standard, but there is no consensus in the literature on the gold standard for diagnosing lymphoedema. One of these studies (Bundred et al. 2015) has been shown to have limitations in terms of the methodology and calculations used in the detection of lymphoedema with the L‑Dex U400 (Ward et al. 2015).

A third study (Soran et al. 2014) examined whether the L‑Dex U400 can be used to detect subclinical lymphoedema, which is difficult to detect with standard methods such as measurement of limb circumference. However, the sample size was relatively small and because the control group was not prospectively monitored for preclinical lymphoedema, there was no measurement of the diagnostic accuracy of the L‑Dex U400.

A prospective study on the L‑Dex U400 and other methods of diagnosing lymphoedema is currently being done in the NHS (Bundred et al. 2013). This and future randomised controlled trials should add to the evidence base for the diagnostic accuracy of the L‑Dex U400 for lymphoedema associated with breast cancer treatments.

Table 1 summarises the clinical evidence as well as its strengths and limitations.

Table 1. Summary of included studies

Barrio et al. (2015)
Study size, design and location	A prospective observational study based in US of 186 women (>18 years) with early-stage breast carcinoma who had planned breast and axillary surgery (SLNB or ALND).
Intervention and comparator(s)	Intervention: L‑Dex U400 Comparator: volume displacement.
Key outcomes	For all patients (n=13) who developed lymphoedema: 13 women developed lymphoedema during the study period (as measured by volume displacement). Only 4 were measured as having an abnormality by the L‑Dex before diagnosis with volume displacement (sensitivity=31%; specificity=88%). The L‑Dex ratio was abnormal in 12 of the 13 patients at the point of diagnosis with volume displacement (sensitivity=92%). For all patients (n=186): Of 28 abnormal volume displacement measurements, 7 were normal according to the L‑Dex (sensitivity=75%; false-negative rate=25%). Of 801 normal volume displacement measurements, 56 were abnormal by L‑Dex (specificity=93%, false-positive rate=7%). Overall the NPV=99% and PPV=27% for L‑Dex. There was also poor correlation between change in volume displacement and change in L‑Dex measurements (correlation coefficient=0.31 at 3 months and 0.21 at 6 months). For subgroup of patients undergoing SLNB (n=151): Of 2 abnormal volume displacement measurements (occurring in 1 patient), the L‑Dex result was normal in both, corresponding to a sensitivity of 0%. Specificity was 96% with a false-positive rate of 4% (28 false-positive measurements). NPV=99.7% and PPV=0%.
Strengths and limitations	Prospective study design; direct comparison against a current standard diagnostic. Low incidence of lymphoedema, particularly for SLNB patients (n=1) leading to large variance in estimates of sensitivity.
Bundred et al. (2015)
Study size, design and location	A prospective observational study based in UK of 612 women having surgery for breast cancer with follow-up measurements of at least 6 months.
Intervention and comparator(s)	Intervention: L‑Dex U400 Comparator: 350S Perometer (Pero-System, Germany).
Key outcomes	52 women had developed lymphoedema (detected by perometer) at 6 months. L‑Dex detected 91 false positives, 38 true positives, 14 false negatives and 469 true negatives. Sensitivity=73% (95% CI 59 to 84) Specificity=84% (95% CI 80 to 87) There was moderate correlation between changes in perometer and L‑Dex measurements both at 3 months (r=0.4) and 6 months (r=0.6). At 18 months post-surgery 71 women had developed lymphoedema detected by perometer, whereas 126 cases were identified by L‑Dex.
Strengths and limitations	Prospective study design; large sample size; direct comparison against a current standard diagnostic. Low incidence of lymphoedema; short follow-up time.
Soran et al. (2014)
Study size, design and location	A prospective observational study based in US of 180 women with breast cancer who had surgery (ALND).
Intervention and comparator(s)	Intervention: L‑Dex U400 used to monitor lymphoedema status every 3 to 6 months for first year post-surgery and annually thereafter. Patients with diagnosed subclinical lymphoedema were proactively treated to avoid progression. Comparator: no monitoring. Circumferential arm measurements used to detect clinical lymphoedema at 12 months post-surgery.
Key outcomes	Subclinical lymphoedema was diagnosed in 28 patients (38.9%) monitored with L‑Dex and 2 of these patients (2.8%) progressed to clinical lymphoedema. In the control group 16 patients (36.4%) developed clinical lymphoedema. Therefore, incidence of clinical lymphoedema was 8 times higher in the control group (p<0.001), indicating that early detection with L‑Dex, and subsequent treatment, may reduce progression to clinical lymphoedema.
Strengths and limitations	Prospective study design. No direct comparison of L‑Dex with comparator for diagnosis of clinical lymphoedema.
Abbreviations: ALND, axillary lymph node dissection; CI, confidence interval; NPV, negative predictive value; PPV, positive predictive value; SLNB, sentinel lymph node biopsy.

Recent and ongoing studies

A search on clinicaltrials.gov revealed 1 ongoing trial investigating the diagnostic accuracy of the L‑Dex U400:

A 5‑year, multi-site randomised clinical trial in the US and Australia involving 1,100 patients. There will be a 3‑year follow-up to assess the impact of the L‑Dex U400 in the prevention of lymphoedema. (https://clinicaltrials.gov/ct2/show/NCT02167659).

There is also a large ongoing NIHR clinical trial of bioimpedance using the L‑Dex U400 and other methods for the early detection of lymphoedema. Preliminary results have been reported in an abstract (Bundred et al. 2013).