Evidence-Based Outcomes

Key Points

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The surgical treatment of lymphedema has not been evaluated in randomized clinical trials; therefore, the level of current evidence does not justify the widespread adoption of surgery as the standard of care for lymphedema.
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Complete decongestive therapy remains the only lymphedema treatment that is supported at the highest level of evidence.
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Health-related quality of life is a multidimensional construct that encompasses physical, functional, emotional, and social well-being parameters.
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A variety of quality of life instruments have been used to capture outcomes in lymphedema patients, but some of these instruments were not sensitive to lymphedema-specific outcomes.
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Lymphedema-specific symptom assessment tools may be more sensitive than other instruments to clinically meaningful changes in patients with lymphedema.

Introduction

Lymphedema continues to be a significant health issue for cancer survivors, as shown by the 2006 and 2010 LiveStrong Cancer Survivor Surveys. Among the 6593 survivors of various types of cancer who completed the questionnaires, lymphedema was the sixth most-frequently reported physical issue; lymphedema was an increasing concern for 21% of respondents in 2006 and for 25% of respondents in 2010. Of the respondents, 53% had their cancer treated with surgery or radiation, with or without adjuvant systemic therapy.

Standard-of-care lymphedema treatment is a management-based program providing symptomatic relief but requiring lifelong compression, self-massage, and in some cases regular visits to a lymphedema therapist for bandaging, education, and manual lymphatic drainage. Although some surgical management techniques for the treatment of lymphedema offer patients an opportunity to forgo lifelong treatment and in some cases to forgo ongoing compression, little evidence exists for the long-term efficacy of these relatively novel procedures.

Because quality of life (QOL) outcomes have become a subject of increasing focus as primary or secondary outcomes in most clinical trials, a variety of general, malignancy-specific, and symptom-specific self-report instruments have been developed and used to assess QOL and symptoms in patients who have or are at risk for lymphedema. This chapter will provide an overview of the levels of evidence used in plastic surgery research, the published evidence for the surgical treatment of lymphedema, the assessment of patient-centered outcomes, and specific QOL and symptom assessment tools that have been used to evaluate patients with lymphedema.

Level of Evidence

Definitions

The Center for Evidence-Based Medicine has created a document that categorizes the levels of evidence available for current clinical practices. The highest level of evidence is level 1A, which is evidence derived from a systematic review of randomized controlled trials, and the lowest level of evidence is level 5, which is expert opinion without clinical basis. Each level has clearly defined criteria ( Table 22.1 ).

Table 22.1

Level of Evidence Scoring System

Level	Evidence for Therapy/Treatment/Prevention
1a	Systematic review with homogeneity of randomized controlled trials
1b	Individual randomized controlled trials with narrow confidence intervals
1c	All-or-none case series
2a	Systematic review with homogeneity of cohort studies
2b	Individual cohort study
2c	Outcomes research; ecological studies
3a	Systematic review with homogeneity of case studies
3b	Individual case-control study
4	Case-series and poor-quality cohort or case-control studies
5	Expert opinion without explicit critical appraisal

From Sullivan et al. Plast Reconstr Surg 2011 Jul;128(1):311–4.

These levels of evidence have been modified to specifically address the levels of evidence used in plastic and reconstructive surgery articles. This modified schema first classifies articles as diagnostic, therapeutic, or prognostic and then further classifies them using the Center for Evidence-Based Medicine levels 1 through 5. The highest-level evidence is defined as evidence arising from a high-quality cohort study with adequate power or from a systematic review of multiple studies, and the lowest-level evidence is defined as expert opinion. The levels vary between the diagnostic, therapeutic, and prognostic-associated sub-classifications but share general characteristics. For therapeutic studies, the highest level of evidence comes from high-quality single- or multicenter randomized controlled trials with appropriate power; for diagnostic studies, the highest level of evidence comes from cohort studies validating a diagnostic test using a gold-standard test as a comparison; and for prognostic/risk studies, the highest level of evidence comes from prospective cohort or comparative analyses. In each category, a systematic review of the study types at the highest level for that category can also be classified as the highest level of evidence. The lowest level of evidence in each category comes from expert opinions or consensus documents based on the evaluation of case studies ( Table 22.2 ).

Table 22.2

Plastic Surgery-Specific Criteria for Levels of Evidence

Level	Therapeutic Studies	Diagnostic Studies	Prognostic/Risk Studies
I	High-quality, multicenter or single-center randomized controlled trial with adequate power	High-quality, multicenter or single-center cohort study validating a diagnostic test with a ‘gold’ standard as a reference in a series of consecutive patients	High-quality, multicenter prospective cohort or comparative study with adequate power
	Systematic Review of the Above Studies Qualifies as Level I Evidence
II	Lesser-quality randomized controlled trial, prospective cohort or comparative study	Exploratory cohort study developing diagnostic criteria (with a ‘gold’ standard as a reference) in a series of consecutive patients	Lesser-quality prospective cohort or comparative study; retrospective cohort or comparative study; untreated controls from a randomized controlled trial
	Systematic Review of the Above Studies Qualifies as Level II Evidence
III	Retrospective cohort or comparative study	Diagnostic study in non-consecutive patients without consistently applied ‘gold’ standard	Case-control study
	Systematic Review of the Above Studies Qualifies as Level III Evidence
IV	Case series with pre/post-test or post-test only	Case-control study or any above-mentioned study without a ‘gold’ standard	Case series with pre/post-test or post-test only
V	Expert opinion developed via consensus; case report or clinical example; evidence based on physiology, bench research, or ‘first principles’	Expert opinion developed via consensus; case report or clinical example; evidence based on physiology, bench research, or ‘first principles’	Expert opinion developed via consensus; case report or clinical example; evidence based on physiology, bench research, or ‘first principles’

Adapted from Sullivan et al. Plast Reconstr Surg 2011 Jul;128(1):311–4.

NonSurgical Treatment of Lymphedema

The traditional, gold-standard treatment for lymphedema remains complete decongestive therapy (CDT). In the treatment phase of CDT, trained lymphedema therapists apply multiple modalities including manual lymph drainage, multilayer short-stretch compression bandaging, therapeutic exercises, skin care, elastic compression, and education in self-maintenance. After the treatment phase, which usually lasts three to eight weeks, the patient is expected to continue into the maintenance phase, which includes self-administered lymphatic drainage, exercise, skin care, and compression garments.

A recent systematic review by Lasinksi et al. includes eight randomized controlled trials and 10 prospective cohort studies that examined the outcomes associated with CDT, placing this review at the highest level of evidence. This study utilized both data collected from studies and data described in previously published reviews. The authors concluded that those studies were moderately strong but lacked consistent, objectively collected data and that several of the studies that did describe consistent interventions often bundled CDT with other interventions. Findings from these data indicate that CDT is effective in reducing limb volume. However, many treatments are only evaluated as a bundled therapy (e.g., manual lymph drainage and bandaging) which makes it difficult to determine the overall efficacy of a single component of the CDT treatment schema.

Nonsurgical treatments other than CDT can be considered for the treatment of lymphedema. A systematic review of complementary, alternative, and other non-CDT lymphedema treatments found that treatments like these were widespread but poorly supported by evidence. In this review, the lymphedema therapies were categorized as either physical agents or modalities of contemporary value. The physical agent modalities included ultrasound therapy, electrically stimulated lymphatic drainage, high-voltage electrical stimulation, diathermy, low-level laser therapy, hyperbaric oxygen therapy, elastic taping, and acupuncture. Among the modalities of contemporary value were internationally designed at-home units devised to complete manual lymph drainage through circular massage motions, aqualymphatic therapy, and extracorporeal shockwave therapy. The evidence supporting the use of any of these therapies remains limited. Most of these studies were completed with a small convenience sample (level 2) or a case series (level 4) and have not been replicated. Also, very few of these studies used completely objective measures of limb volume reduction, such as circumference, perometry, water displacement, or bioimpedance; subjective measures including symptom assessment and clinical examination were used to identify the pre- and post-treatment changes which limit the validity of the data.

Surgical Treatment of Lymphedema

Surgical treatment of lymphedema has become more widely available and is used primarily in the treatment of chronic, progressive lymphedema that remains refractory to standard treatment protocols. Because of the paucity of published high-level studies evaluating the long-term outcomes following surgical treatment of lymphedema, this type of treatment remains controversial and is considered experimental in many countries, including the US.

In 2011, a systematic review on the surgical treatment of lymphedema cited a lack of evidence due primarily to small patient populations, failure to use objective measurement criteria for limb volume change, and a lack of long-term follow-up. Summaries of the literature included in the systematic review have been updated through February 2014 and are presented in Tables 22.3–22.6 . Subsequent systematic reviews have been published evaluating the efficacy of microsurgery and tissue transplantation in treating lymphedema; these reviews have found mixed outcome results.

Table 22.3

Summary of Published Literature Related to Excisional Procedures for the Treatment of Lymphedema

Author (Year)	Study Design	Number of Patients	Lymphedema Site	Specific Surgical Procedure	Follow-Up Time, Months	Measurement Technique	Volume Reduction, %	QOL Tool Used
Kim et al. (2004)	Retrospective	20	Lower extremity	Excision	17.8	Volumeter	16%	None
Modolin et al. (2006)	Prospective	17	Penis/scrotum	Excision	72	NR	NR	None
Lee et al. (2008)	Retrospective	22	Lower extremity	Excision	48	Infrared optometric volumetry and circumference	NR	Mentions QOL but no instrument
Salgado et al. (2009)	Prospective	11	Upper extremity	Excision with preservation of perforators	17.8	Circumference	21	None
van der Walt et al. (2009)	Retrospective	8	Lower extremity	Modified Charles procedure	27	NR	8.5 kg	None
Karri et al. (2011)	Retrospective	27	Lower extremity	Charles procedure	48	NR	NR	None

NR: not reported; QOL: quality of life.

Modified from Cormier et al., Cancer 2010 Nov 15;116(22):5138–49.

Table 22.4

Summary of Published Literature Related to Liposuction Procedures for the Treatment of Lymphedema

Author (Year)	Study Design	Number of Patients	Lymphedema Site	Specific Surgical Procedure	Follow-Up Time, Months	Measurement Technique	Volume Reduction, %
Liu et al. (2005)	Prospective	11	Upper extremity	Liposuction	^∗	Circumference	^∗
Brorson et al. (2006)	Prospective	35	Upper extremity	Liposuction	12	Water displacement	103
Qi et al. (2009)	Prospective	11	Upper extremity	Liposuction, myocutaneous flap transfer	26	Circumference	18
Damstra et al. (2009)	Prospective	37	Upper extremity	Suction-assisted lipectomy	12	Water displacement	118
Schaverien et al. (2012)	Prospective	12	Upper extremity	Liposuction	36	Water displacement	123
Granzow ^∗∗(2014)	Retrospective	10	Upper extremity (n=6), lower extremity (n=4)	Suction-assisted lipectomy	32	Circumference	111% (UE), 87% (LE)

UE: upper extremity, LE: lower extremity.

Modified from Cormier et al., Cancer 2010 Nov 15;116(22):5138–49.

∗ Abstract only available.

∗∗ Study included a discussion of patients who had tissue transfer and lymphatic venous anastomosis.

Table 22.5

Summary of Published Literature Related to Tissue Transfer Procedures for the Treatment of Lymphedema

Author (Year)	Study Design	Number of Patients	Lymphedema Site	Specific Surgical Procedure	Follow-Up Time, Months	Measurement Technique	Volume Reduction, %
Weiss et al. (2002)	Prospective	12	Upper extremity	Autologous lymphatic tissue transplantation	96	Circumference	22 to 31
Wongtrungkapun (2004)	Prospective	10	Lower extremity	Lymphonodovenous implantation	4.5	Circumference	3.5 cm at knee, 7.37 cm at 16 cm below knee, 2.75 at metatarsal level
Becker et al. (2006)	Retrospective	24	Upper extremity	Lymph node transplantation	96	Circumference	Reduction to normal (n=10), some reduction (n=10), no change (n=2)
Belcaro et al. (2008)	Retrospective case-control	9	Lower extremity	Autologous lymphatic tissue transplantation (n=9) vs. control (n=8)	120	Water displacement	Increase of 13
Hou et al. (2008)	Randomized controlled trial	15	Upper extremity	Autologous bone marrow stromal cell transplantation (n=15) vs. CDT (n=35)	12	Circumference	81
Lin et al. (2009)	Retrospective	13	Upper extremity	Vascularized lymph node transfer	56	Circumference	51
Gharb et al. (2011)	Prospective	21	Upper extremity	Vascularized lymph node transfer	40	Circumference	NR
Cheng et al. (2012)	Prospective	6	Lower extremity	Vascularized lymph node transfer	8.7	Circumference	64% above knee, 64% below knee, 67% above ankle
Cheng et al. (2013)	Prospective	10	Upper extremity	Vascularized lymph node transfer	39	Circumference	40

NR: not reported

Modified from Cormier et al., Cancer 2010 Nov 15;116(22):5138–49.

Table 22.6

Summary of Published Literature Related to Lymphatic Reconstructive Procedures for the Treatment of Lymphedema

Author (Year)	Study Design	Number of Patients	Lymphedema Site	Follow-Up Time, Months	Measurement Technique	Volume Reduction, %
Koshima et al. (2004)	Retrospective	52	Lower extremity	15	Water displacement	42
Matsubara et al. (2006)	Retrospective	9	Lower extremity	21 to 87	Circumference	>5 cm (n=6), 2 cm (n=2), no effect (n=3)
Damstra et al. (2009)	Prospective	10	Upper extremity	12	Water displacement	2
Demirtas et al. (2009)	Retrospective	42	Lower extremity	12	Circumference	59
Campisi et al. (2010) ^∗	Retrospective	1800	Upper and lower extremities	120	Water displacement	56 (83% with 67% reduction)
Chang (2010)	Prospective	20	Upper extremity	18	Perometer	35
Maegawa et al. (2010)	Retrospective	111	Lower extremity	NR	Circumference	Percentage not reported average 872 ml reduction
Mihara et al. (2010)	Retrospective	11	Lower extremity	23.6	Circumference	92
Narushima et al. (2010)	Prospective	14	Upper extremity (n=2), lower extremity (n=12)	809	Circumference	11
Furukawa et al. (2011)	Prospective	9	Upper extremity	17	Circumference	>50 in 77.8% of patients
Yamamoto et al. (2011)	Retrospective	20	Lower extremity	8.9	Circumference	11
Auba et al. (2012)	Prospective	12	Upper extremity (n=7), lower extremity (n=5)	24	Circumference	1.18 cm circumference
Mihara et al. (2012)	Prospective	6	Lower extremity	10	Circumference	NR
Ayestaray et al. (2013)	Prospective	4	Head and neck	12	Circumference	3.7
Boccardo et al. (2013)	Retrospective	23 ^∗∗	Lower extremity	42	Circumference	80
Chang et al. (2013)	Prospective	100	Upper extremity (n=89), lower extremity (n=11)	12 to 36	Perometer	42 (upper extremity) 7 to 42 (lower extremity)

NR: not reported.

Modified from Cormier et al., Cancer 2010 Nov 15;116(22):5138–49.

∗ Selected among duplicate studies with overlapping patients.

∗∗ Study included patients treated in a preventative manner, lymphedema patients included.

Surgical intervention for lymphedema has been widely reported in the literature, but only two such studies were found to use any patient-reported QOL metrics. Among reports of excisional surgical procedures to treat lymphedema, only one study reported any assessment of QOL; however, this study did not report what instrument was used. In a study of 35 patients who received liposuction for the treatment of chronic lymphedema, QOL was evaluated using the Psychological General Well-Being Index (22 items) and the Hospital Anxiety and Depression Scale (14 items). Six months after liposuction, the patients’ total scores and general health scores in the Psychological Well-Being Index had improved since baseline measurements, but this change was not statistically significant. Scores on the Hospital Anxiety and Depression Scale decreased, although the change was not statistically significant, at six months after the surgery but returned to their baseline levels at 12 months after the surgery.

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