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Lymphatic venous anastomosis (LVA) for treatment of secondary arm lymphedema. A prospective study of 11 LVA procedures in 10 patients with breast cancer related lymphedema and a critical review of the literature

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Lymphatic venous anastomosis (LVA) for treatment of secondary arm lymphedema. A prospective study of 11 LVA procedures in 10 patients with breast cancer related lymphedema and a critical review of the literature
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  REVIEW Lymphatic venous anastomosis (LVA) for treatment of secondaryarm lymphedema. A prospective study of 11 LVA proceduresin 10 patients with breast cancer related lymphedemaand a critical review of the literature R. J. Damstra   H. G. J. Voesten   W. D. van Schelven   B. van der Lei Received: 3 January 2008/Accepted: 29 January 2008/Published online: 13 February 2008   Springer Science+Business Media, LLC. 2008 Abstract  Objective  The incidence of breast cancer relatedlymphedema (BCRL) varies between 7-35% depending onthe combination of treatment modalities. Early detection of BCRL is crucial in order to start an effective non-operativetreatment program. Because of the lack of prospectiveresearch on this topic, this study was undertaken to pro-spectively determine the effect of Lympho VenousAnastomosis (LVA) on BCRL and to review the currentliterature.  Study design and methods  Ten patients who werepreviously treated for breast cancer by surgery, radiother-apy, and chemotherapy, and were unresponsive to 12-weeksof non-operative treatment, underwent an LVA procedure(Degni-Cordeiro). Objective measurements were gatheredfor circumferential measurement and water volumetry, andquality of life. Various types of lymphoscintigraphy werecarried out pre-operatively and post-operatively at 3 and 12months. Treatment was embedded in a multidisciplinarysetting.  Results  Post-operative volume measurements ini-tially showed a 4.8% reduction of lymphedema at 3 monthsand a 2% reduction after one year. Various scintigraphicparameters showed some improvement. Quality of lifequestionnaires reported minimal improvement. Reviewingthe literature, only retrospective studies were found; thesereported varying results for LVA procedures. The selectionof patients, classification of lymphedema, indications andtypes of LVA, and additional therapeutic options wereheterogeneous, not comparable, and lacked a validatedmethod of effect-assessment.  Conclusions  Our resultsshowed a minimal reduction in volume of lymphedemafollowing LVA; in the literature, there was no convincingevidence of the success of LVA. Non-operative treatmentand elastic stockings are still preferred by most patientswith lymphedema, especially in early stages with fewirreversible changes. Keywords  Lympho-venous anastomosis (LVA)   Microsurgery    Evidence-based medicine   Lymphoscintigraphy    Inverse water volumetry   Review    Breast cancer related lymphedema Introduction Lymphedema is a chronic disease caused by impairment of the lymphatic transport capacity, resulting in edema, excessof tissue proteins, and in latter stages, inflammation andirreversible changes such as fibrosis and excess of adiposetissue [1]. Lymph transport impairment and clinical signsof lymphedema can be acquired (secondary) or congenital(primary). Treatment of lymphedema is challenging.Therapeutic approaches consist of both non-operative andoperative methods. The overwhelming majority of patientscan effectively be treated by non-operative means such ascomplex decongestive therapy (CDT) in combination with R. J. Damstra ( & )Department of Dermatology, Phlebology and Lymphology,Nij Smellinghe Hospital, Compagnonsplein 1,9202 NN Drachten, The Netherlandse-mail: r.damstra@nijsmellinghe.nlH. G. J. VoestenDepartment of Surgery, Nij Smellinghe Hospital,Drachten, The NetherlandsW. D. van SchelvenDepartment of Nuclear Medicine, Medical Centre Leeuwarden,Leeuwarden, The NetherlandsB. van der LeiDepartment of Plastic Reconstructive, Aesthetic and HandSurgery, University Medical Centre Groningen, Groningen,The Netherlands  1 3 Breast Cancer Res Treat (2009) 113:199–206DOI 10.1007/s10549-008-9932-5   p  e  e  r  -   0   0   4   7   8   3   1   3 ,  v  e  r  s   i  o  n   1  -   3   0   A  p  r   2   0   1   0 Author manuscript, published in "Breast Cancer Research and Treatment 113, 2 (2008) 199-206" DOI : 10.1007/s10549-008-9932-5  manual lymphatic drainage, bandaging, physical exercises,skin care and elastic stockings. In the long lasting main-tenance phase, therapeutic elastic stockings are mandatory.The goal of all non-operative treatment modalities is toreduce capillary filtration, improve drainage of interstitialfluid and macromolecules, and therefore reduce swelling,inflammation, recurrence of erysipelas, and improve qual-ity of life [2]. Operative treatment is only indicated in a fewcases as a last resort.Many reconstructive techniques have been described,such as lymphovenous anastomosis (LVA) [3], lympho-venous-lymphatic (LVL) transplant (especially in thepresence of venous hypertension [4]), and forms of lymphvessel transplantation [5]. LVA has been the mostfrequently used type of operation.So far, most studies on LVA have both demonstrated alack of significant volume reduction and considerable het-erogeneity in the study populations. Therefore, we decidedto evaluate the effectiveness of LVA in the treatment of one-sided breast cancer related lymphedema in a limitedprospective study using objective, validated measurementmethods with very strict inclusion criteria. These resultswill be discussed along with a review of the literature. Patients, materials and methods Study design and populationThe study was conducted in the Lymphedema Departmentof Nij Smellinghe Hospital in Drachten, The Netherlands,from 1999 to 2002. A systematic review of English andGerman language literature retrieved from MEDLINE,COCHRANE and Cinahl databases up to April 2007 wasperformed. The articles were classified in levels of scien-tific evidence according the criteria for evidence-basedmedicine.The study population consisted of 10 BCRL patientswith severe lymphedema and persistent complaints, notresponsive to maximal non-operative lymphedema treat-ment and who met the inclusion criteria for operativetreatment. The patients were hospitalized in the lymphe-dema clinic to undergo a LVA according to our protocol.Inclusion and exclusion criteriaIn order to be included in this prospective study, patientswith unilateral breast cancer related lymphedema had tomeet the following criteria: •  No volume reduction after 3 months of complexdecongestive treatment including manual lymphdrainage, compression therapy, and physiotherapy,with persistent complaints such as heaviness, pain,shoulder function impairment, and recurrent attacks of erysipelas •  Persistent volume excess of more than 800cc measuredby inverse water volumetry •  Proven scintigraphic signs of obstruction by absence of liver uptake and highly pathological transport index •  No recurrent malignancy •  Good patient compliance and willingness to weartherapeutic elastic stockings •  Operability.Data collection and lymphoscintigraphyAll patients underwent objective measurements withvalidated methods. The quality of life was measured pre-operatively and 6 months postoperatively using thevalidated SF-36 quality of life assessment questionnaire[6]. Volume measurements were performed prior to LVAand at 3, 6, 12, and 24 months after LVA. Volumetry wasperformed with the inverse water volumetry method (goldstandard) [7]. Furthermore, indirect circumferential mea-surements were taken according the Herpertz method [8]for unilateral swelling, correlating the difference betweenthe lymphedemic limb and the normal one.The following clinical classification [9] (Campisi) wasused:Stage 1a: no edema, in spite of the presence of lymphaticcirculation anomalies (e.g. due to mastectomy andaxillary/inguinal lymphadenectomy; no difference involume and consistency between limbs).Stage 1b: same as stage 1a with mild edema, returning tonormal after night rest.Stage 2: permanent edema, spontaneously regressingonly with antideclivous position and night restStage 3: permanent edema, not spontaneously regressingwith antideclivous position, and ingravescent (erysipe-las/cellulitis)Stage4:fibrolymphedema(initiallymphostaticverrucosis)with ‘‘column’’ limbStage 5: elephantiasis with severe limb deformation(including sclero-indurative pachydermitis and lympho-static verrucosis)Scintigraphic protocolUnilateral lymphoscintigraphy was performed with focuson the liver uptake. On the anterior and posterior images, 200 Breast Cancer Res Treat (2009) 113:199–206  1 3   p  e  e  r  -   0   0   4   7   8   3   1   3 ,  v  e  r  s   i  o  n   1  -   3   0   A  p  r   2   0   1   0  counts were determined in the liver and in the total field of view respectively. Subsequently, geometric means werecalculated for the liver and the total field of view. The liverfraction was calculated. In cases of very early detection of liver uptake, the possibility exists for technical failureresulting from unintentional intravenous injection of radioactive tracer: the fast venous transport causes thetracer to show up in the liver very early. In the case of correct subcutaneous administration of the radioactivetracer, the liver can be visualized after some time throughuptake via blood vessels. The radioactive tracer reaches theblood stream either via the thoracic duct or, in the case of afunctioning lymphatic venous anastomosis, via this shunt.We defined any uptake at 120 and 180 minutes as sign of lymphatic drainage from the arm, which was preopera-tively absent. Results were analyzed preoperatively andone year postoperatively.In unilateral lymphoscintigraphy,  99m Tc-Nanocolloidwas administered subcutaneously in the second interdigitalspace of the edematous arm. A dose of 80 MBq and avolume of 0.1 ml were used. Mobilization was standard-ized by asking the patient to make a fist repetitively duringa fixed period of time. During the first 40 min following theinjection, dynamic images were taken, including the entirearm, the axilla and the liver. Then images were made 60,120, and 180 min after the injection.The images were interpreted in three ways: visual(qualitative) interpretation, semi-quantitative interpretationusing the Transport Index, and quantitative interpretationthrough calculation of the liver fraction after 60, 120, and180 min.In clinical practice, visual interpretation is the methodmost often used, as it is easy to perform; however, smalldifferences between pre and postoperative studies may bedifficult to recognize.Kleinhans et al. have described the Transport Index[10]. In this index, five parameters describe the lymphflow: lymphatic transport kinetics (K), distribution pattern(D), time lapse to appearance of lymph nodes (T in min-utes, multiplied by 0.04), assessment of lymph nodes (N),and assessment of lymph vessels (V). Each parameter canbe given a score from 0 to 9, where 0 means that there areno abnormalities and 9 indicates that the condition for agiven parameter could not be worse. The five scores arethen added, resulting in the Transport Index, which canvary from 0 (normal) to 45 (most abnormal).Operating techniqueAll LVA procedures were carried out under general anes-thesia. A skin incision was made in the upper arm, about7–10 cm above the elbow. No pneumatic tourniquet wasused for exsanguination. Intradermal and subcutaneousinjections of Methylene Blue were used 1 to 2 cm distal tothe skin incision lines to outline the lymphatic system. Alloperative procedures were carried out by an experiencedmicro-vascular surgeon (BvdL) using an operating micro-scope. After skin incision, careful dissection wasperformed to identify small-sized veins (1–3 mm indiameter). After identifying a suitable vein, and collectinglymphatics (including some lymphatic vessels), lymphaticcapillaries were dissected in the surrounding area. Thediameters of these lymphatic vessels were 0.3 mm or less.With micro instruments, end-to-side anastomoses weremade according to the Degni-Cordeiro procedure [11]using 11–0 micro sutures; at least 3–4 anastomoses weremade. Average completion time of the LVA procedurewas about 60 min. Antibiotics were used perioperatively;the extremity was bandaged and elevated at night. Elas-tic stockings were continued permanently during thefollow-up. Results A total of 11 LVA procedures in 10 female patients wereincluded in our study in the period from 1998–2002. Themean age of the patients was 58.7 years ( D  46–68). Allpatients had stage 3 breast cancer related lymphedemaaccording to Campisi, and were treated with mastectomy,axillary lymph node dissection, radiotherapy, and chemo-therapy. Lymphedema was present for a mean period of 5.3 years ( D  3–14 years) before LVA. None of the patientshad responded sufficiently to our standardized conservativetreatment program over 3 months. After removal of anypitting component, no further volume reduction could beachieved.Quality of lifeAfter 6 months, 5 of 10 patients had subjective relief of their complaints according to the SF-36 questionnaire.Volumetry (See also Table 1)After 3 months, there was a slight but insignificant reduc-tion of volume. After one year this reduction diminished toalmost zero (Table 1). The preoperative volume differencebetween both arms was 988cc.After one year, the mean volume difference was 1075cc( D 500–1856).The Herpertz circumferential measurement demon-strated improvement of 4.8% after one year. The initial Breast Cancer Res Treat (2009) 113:199–206 201  1 3   p  e  e  r  -   0   0   4   7   8   3   1   3 ,  v  e  r  s   i  o  n   1  -   3   0   A  p  r   2   0   1   0  volume reduction with water displacement of 16% at threemonths was lost after one year, when no more than 2%volume difference was observed.Scintigraphy (see also Table 1)According to the Kleinhans transport index, there was nosignificant difference in transport before and one year afterthe operation: 43.0 ( D  28–45) versus 42.2 ( D  30–43).Qualitative scintigraphic observation demonstrated anabsence of lymph transport, dermal backflow and few signsof any organized transport, comparable with longstandinglymph-obstruction. In one patient, a lymph node in theelbow was visualized. After one year, a quantitative scin-tigraphical evaluation demonstrated no liver uptake afterLVA, as compared with an initial lymphoscintigraphy.Long term follow-upBeyond the initial study design, at long term follow up in2007 (mean follow-up 8 years), 2 patients had stablelymphedema using elastic stockings, 3 patients had died of metastasis, 4 patients had complete volume reduction aftercircumferential suction-assisted lipectomy(Bro¨rsonmethod[12]) and 1 patient was lost to follow up. The main charac-teristics and results of 10 patients are presented in Table 1. Discussion This prospective study clearly demonstrates that, althoughthere was an initial period of relief of the subjectivecomplaints in 5 of 10 patients, there were no significantimprovements after LVA in our series of patients withchronic lymphedema; neither volume measurements norscintigraphic measurements showed any effect.When reviewing the literature of the last decades (seeTable 2), there is a striking lack of prospective and com-parative studies concerning the effect of LVA on chroniclymphedema. All studies reviewed initially used non-operative treatment by CDT for a period ranging from3 days up to 6 months. Although this might create a biaswhen selecting patients for LVA, the alternative is thatmany patients would have unnecessary operative treatmentwith perhaps detrimental effects. Most patients with earlystages 1–3 of lymphedema can be treated successfully withCDT [22, 23]. Moreover, in many studies information is missing about the follow-up protocol and many do notreport whether or not elastic stockings are mandatory afteran LVA procedure. Table 1  Summary of resultsMean age ( n  =  10) 58.7 Years ( D  46–68)Duration of lymphedema 5.4 years ( D  3–14)Clinical classification by Campisi Stage 3:  n  =  10  Inverse water volumetry Total volume pre OP 4253 cc ( D  2817–6456)Volume difference normal side pre OP 988 ( D  532–1400)Volume difference normal side at 3 months 841 ( D  232–1256)Volume difference normal side at 6 months 994 ( D  500–1789)Volume difference normal side at 12 months 1075 ( D  500– 1856)  Herpertz method at 0–12 months: (at four points) Mean Volume difference pre OP 35.2% ( D  20–50%)Mean volume difference 12 months 33.5% ( D  18–49%) Visual signs lymphoscintigraphy Dermal back flow 10Lymph vessels 0Lymphnode in the elbow 1 Kleinhans transport index at 0–12 months TI pre OP 43.0 ( D  28–45)TI post OP 42.2 ( D  30–43)Liver uptake at 0–12 monthsLC pre OP (after 120 and 180 min) 0LC post OP (after 120 and 180 min) 0SF 36 questionnaire 0– 6 months Slight subjective improvement in 5 patients who felt less disabled202 Breast Cancer Res Treat (2009) 113:199–206  1 3   p  e  e  r  -   0   0   4   7   8   3   1   3 ,  v  e  r  s   i  o  n   1  -   3   0   A  p  r   2   0   1   0  Table 2  Literature on the effects of LVAFirstauthorStudy Method of volume measurement Lymphoscintigraphy Intervention  N   AddionaltreatmentFollow up(month)Results O’Brien[13]RetroSLA/LCTF(0,1)Volumetry4 point measurementall pre-threatmentNo LVA (10 withreduction surg)40; Follow-up in n  =  35 32 arm/3legNo special care 18.6  N   =  21 32%  +  N   =  14: 18%  * Filipetti[14]RetroSLACTF?Class 1: poorClass 2: fairClass 3: goodNM LVA armSome withfasciotomy19 NM Total: 2218 just LVA13/22: class 2/3 [ 50%  +  ( n  =  3) \ 50%  +  ( n  =  7)0  *+  ( n  =  8)VanCruchten[15]RetroSLACTF( & )Volume/circumferenceStaging according to Anderson (AC)NM LVA arms 1400 Some weeksgarment60 St 1: 81%  +  n  =  792St 2: 69%  +  n  =  413St 3: 57  +  n  =  120St 4: 31%  +  n  =  75Campisi[16]RetroPL/SLA/LCTF( & )Volumetry Yes LVA 664 adults48 childrenElastic stocking 60 Campisi class: St 1:100%  + St 2: 98%  + St 3: 63%  + St 4: 46%  + Huang [17] RetroPL/SLA/LCTF(0)Volumetry NM LVA (filariasis  + erysipelas)98 (PL/SL)91 leg7 armsNM 26 59.2  ±  29.5%  + Yamamoto[18]RetroPL/SLA/LCTF( & )4 point circumference NM LV ‘‘implant’’ 8arm: 5leg: 3NM 9–27 Wrist:3–5 cm  + Underarm: 1–6 cm  +  (norelative figures)Vignes [9] ProPL/SLLCTF( & )Volumetry, subjective criteria,visualanalog scale (VAS)NM LVA 1310 PL3 SLElastic stockings 49–52 No volume  ± VAS: Bad: 3Intermediate: 5Very good/good: 5Koshima[19]RetroPL/SLLCTF(6)2 messurements: 10 cm above/under kneestaging according to CampisiNon Lymphatico-venularanastomosis52 Elastic stockings 4-24 82.5% effective ( n  =  42)17 from these: [ 4 cm  +  lower legMatsubara[20]RetroSLLCTF(1–130)2 point circumference NM LVA 11 Elastic stockings+physiotherapy21–87  [ 5 cm  +  ( n  =  6)2 cm  +  ( n  =  2)No effect ( n  =  3) Br  e  a  s  t    C  a n c  e r R e  s T r  e  a  t     (   2   0   0   9    )   1  1   3   :  1   9   9  –2   0   6  2   0   3    1  3 peer-00478313, version 1 - 30 Apr 2010
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