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A randomized controlled trial comparing two types of pneumatic compression for breast cancer-related lymphedema treatment in the home

A randomized controlled trial comparing two types of pneumatic compression for breast... Support Care Cancer (2012) 20:3279–3286 DOI 10.1007/s00520-012-1455-2 ORIGINAL ARTICLE A randomized controlled trial comparing two types of pneumatic compression for breast cancer-related lymphedema treatment in the home Caroline E. Fife & Suzanne Davey & Erik A. Maus & Renie Guilliod & Harvey N. Mayrovitz Received: 21 November 2011 /Accepted: 26 March 2012 /Published online: 2 May 2012 The Author(s) 2012. This article is published with open access at Springerlink.com Abstract calculations, and tissue water was determined based on meas- Purpose Pneumatic compression devices (PCDs) are used urements of the arm tissue dielectric constant (TDC). in the home setting as adjunctive treatment for lymphedema Results The APCD-treated group experienced an average of after acute treatment in a clinical setting. PCDs range in 29% reduction in edema compared to a 16% increase in the complexity from simple to technologically advanced. The SPCD group. Mean changes in TDC values were a 5.8% objective of this prospective, randomized study was to deter- reduction for the APCD group and a 1.9% increase for the mine whether an advanced PCD (APCD) provides better out- SPCD group. Conclusion This study suggests that for the home mainte- comes as measured by arm edema and tissue water reductions compared to a standard PCD (SPCD) in patients with arm nance phase of treatment of arm lymphedema secondary to breast cancer therapy, the adjuvant treatment with an APCD lymphedema after breast cancer treatment. Methods Subjects were randomized to an APCD (Flexi- provides better outcomes than with a SPCD. touch system, HCPCS E0652) or SPCD (Bio Compression . . 2004, HCPCS E0651) used for home treatment 1 h/day for Keywords Lymphedema Pneumatic compression devices . . 12 weeks. Pressure settings were 30 mmHg for the SPCD Breast cancer Manual lymphatic drainage Flexitouch® and upper extremity treatment program (UE01) with stan- system Bio compression 2004 sequential circulator dard pressure for the APCD. Thirty-six subjects (18 per group) with unilateral upper extremity lymphedema with at least 5% arm edema volume at the time of enrollment, com- Introduction pleted treatments over the 12-week period. Arm volumes were determined from arm girth measurements and suitable model Lymphedema is a condition resulting from lymphatic dys- function in which persistent swelling exists due to an ab- normal accumulation of protein-rich fluid in an extremity or other body region and is accompanied by marked subcuta- : : C. E. Fife (*) E. A. Maus R. Guilliod neous and skin changes as the condition worsens [1]. Pri- Department of Internal Medicine, Division of Cardiology, mary lymphedema is caused by the abnormal development University of Texas Health Science Center, Memorial Hermann of the lymphatic system and may present at birth, during late Center for Wound Care and Lymphedema Management, 6431 Fannin, MSB 1.247, adolescence, or in early adulthood. Secondary lymphedema Houston, TX 77030, USA results from extrinsic damage or obstruction of the lym- e-mail: Caroline.E.Fife@uth.tmc.edu phatics. In developed countries, breast cancer treatment is recognized as the major cause of secondary lymphedema S. Davey Healing Hands of Lymphatics, [1–3]. The incidence of breast cancer-related lymphedema Hallandale Beach, FL, USA rises dramatically from 3 to 15% after sentinel node biopsy, to 10–20% after complete axillary dissection, and 30 to 50% H. N. Mayrovitz with subsequent radiotherapy [4–7]. Recent data obtained College of Medical Sciences, Nova Southeastern University, from fluorescent lymphatic imaging suggests that some Ft. Lauderdale, FL, USA 3280 Support Care Cancer (2012) 20:3279–3286 patients developing secondary lymphedema may have had a for long-term, as treatment durations ranged from 2 to genetic predisposition to lymphatic malfunction [8, 9]. Cur- 6 hours daily [26] and/or were limited to lower extremity rently, no cure exists for lymphedema, so treatment aims to lymphedema [19, 24]. One comparative study has been ameliorate the swelling, lessen its severity and symptoms, conducted to date regarding APCDs. A pilot RCT investi- and impede progression. Effective long-term treatment strat- gated the home maintenance phase of ten patients who had egies are, therefore, crucial. unilateral breast cancer-associated lymphedema of the arm The traditional initial treatment for lymphedema is com- by comparing self-MLD with an APCD for 1 h each day for plete decongestive therapy (CDT), which consists of manual 14 days followed by crossover to the other treatment with a lymphatic drainage (MLD), short-stretch compression ban- 1-week washout period before each treatment [27]. Post- daging, decongestive exercises, and skin care [10]. While treatment arm volume and patients’ mean weight signifi- this regimen works effectively for most patients when they cantly decreased after using the APCD but not after self- are treated in a clinical setting by a well-qualified therapist, administered MLD [27]. ultimately it is necessary for the patient to attempt to main- Despite development of some clinical consensus that tain the gains and manage this life-long condition in a home APCDs may yield better outcomes for some patients than setting. Successful transfer to the home care setting is chal- simple PCDs [28, 29], further published evidence is lacking. lenging. Many patients find the procedures, particularly Based on the theoretical advantages potentially offered by those for self-MLD and bandaging, time-consuming and an APCD as supported by prior literature, we hypothesized difficult to carry out, especially if they have physical limi- that an APCD would result in better outcomes than less tations from comorbidities. Poor patient adherence to pre- advanced systems when used in the home environment. scribed home treatments can result in failure to maintain The specific goal of this study was to test this hypothesis progress and may likely negate gains achieved during pre- by evaluating and comparing changes in arm edema volume vious clinical treatments. and local tissue water content achieved with the use of either One treatment adjunct that may aid the patient in the an APCD or standard PCD (SPCD) system. home management setting is use of pneumatic compression devices (PCDs). PCDs utilize an air compressor unit that attaches to a garment or series of garments. The garment Materials and methods chambers sequentially inflate and deflate applying pressure against the skin thereby creating a treatment effect. PCDs This study was a prospective, randomized controlled trial in range from simple single-chamber or multichamber devices which patients were consented and randomized in a 1:1 ratio with limited adjustability, to advanced devices with more to either a SPCD (Bio Compression 2004 Sequential Circu- garment options and a wide array of treatment options and lator PCD, Bio Compression Systems, Moonachie NJ, adjustability to address different clinical needs such as fi- USA) or an APCD (Flexitouch system, Tactile Systems brosis, truncal swelling, chronic wounds, or localized swell- Technology, Inc., Minneapolis MN, USA). Each device ing. The adjustability and expanded programs available with was to be used for the home maintenance phase of treatment many advanced PCDs (APCDs) provide for faster and more for secondary upper extremity lymphedema caused by succinct cycles of pressure and relaxation with compression breast cancer treatment. levels better approximating those applied with MLD [11]. Three centers participated in this study: Healing Hands of Some APCDs provide specific garments enabling truncal Lymphatics (Hallandale Beach, FL, USA), Washington treatment, which is deemed fundamental in clinical training Hospital Healthcare System (Fremont, CA, USA), and Me- in MLD technique and is based on lymphatic architecture morial Hermann Hospital (Texas Medical Center, Houston, and animal experimental evidence [11–14]. TX, USA). The trial was approved by the following institu- Validation of treatment and outcome advantages associ- tional review boards (IRBs): Sterling IRB (3139, 02-16- ated with advanced devices in comparison to standard devi- 2009), Washington Hospital Healthcare System IRB (02- ces is lacking. Although, several studies have reported 19-2009), and University of Texas IRB (HSC-MS-10- positive results with use of PCD treatment [15–25], it is 0050, 03-05-2009). This study was conducted in accordance difficult to compare outcomes from the initial body of with US and international good clinical practices (FDA Title evidence regarding early PCDs with more current APCD 21, part 812 and International Conference on Harmonization options. Many of these studies are over 10 years old and guidelines), applicable government regulations and institu- lack sufficient detail about the devices studied to enable tional research policies and procedures. Subjects who were comparisons to aid in device selection or treatment protocol recruited from the participating lymphedema treatment cen- with regard to currently marketed devices, especially the ters had either previously sought or were currently seeking newer PCD technologies [26]. Of significance, most of the treatment for their lymphedema. A total of 36 patients treatment protocols studied were not practical or sustainable (equally divided between standard and APCD use) form Support Care Cancer (2012) 20:3279–3286 3281 the basis of the present report. These 36 patients were fully Tests for baseline group differences in age and BMI, evaluated for edema volume changes after 12 weeks of in- number of nodes that were removed during the subjects’ home treatment and 28 of these patients (also equally divid- initial surgery as well as time between surgery and study ed) were evaluated for changes in arm tissue water content. start showed no significant difference as evaluated via inde- pendent t tests (Table 1). Tests for normality of the data for Eligibility the number of nodes that were removed during the subjects’ initial surgery as well as time between surgery and study Subjects had to be at least 18 years old and able to give start (Shapiro–Wilk test) indicated non-normality (p< informed consent. A confirmed diagnosis of upper extremity 0.001), so this data was tested using the Mann–Whitney lymphedema secondary to breast cancer treatment was test. Results (Table 1) show insignificant differences in both required, and each patient had to have previously completed parameters between groups. Further, tests for baseline group intensive lymphedema treatment (phase I) and discharged to differences in race, affected arm side, dominant arm side, home maintenance (phase II) but the patient must not have type of surgery, radiation treatment, and chemotherapy also received in-home PCD therapy for the past 3 months. Fur- showed no significant difference as evaluated via Pearson’s ther, at least 5% edema volume needed to be present at the Chi Square analyses (Table 1). Thus, with respect to these time of study enrollment. demographic variables, the two groups were well balanced at entry into the study. Baseline data Arm girth measurements Demographic information including age, gender, race, arm dominance, and BMI was collected at baseline. Medical Arm circumferences (girths) were measured with a Gulick II history data collected included type of surgery, chemother- tape measure. The Gulick II tape measure (model 67020; apy, radiation, time since surgery, and number of nodes Country Technology, Inc., Gay Mills, WI) has a tension removed, if applicable. Table 1 summarizes these data for meter attached, so that the tape’s tension can be standardized all subjects separated by randomly assigned groups (SPCD during measurement. The no-stretch, retractable tape is cal- vs. APCD). ibrated to indicate precisely a 4-once tension. During Table 1 Baseline comparison of a b Characteristic APCD (n018) SPCD (n018) p value the advanced and standard PCD groups (APCD, SPCD) Age 63.9±12.2 59.7±12.6 0.315 BMI 28.2±4.6 30.6±7.4 0.258 Months between surgery and study start 105.9±119.7 75.4±73.4 0.815 Number of nodes removed 11.9±8.7 12.6±11.2 0.987 Surgery type 0.441 Mastectomy 12 (67) 15 (83) Lumpectomy 6 (33) 3 (17) Radiation therapy 0.717 Yes 12 (67) 13 (72) No 6 (33) 5 (28) Chemotherapy 0.675 Yes 15 (83) 14 (78) No 3 (17) 4 (22) Race 0.725 Caucasian 10 (56) 13 (72) African American 3 (17) 3 (17) Numbers in parentheses are Hispanic 2 (11) 1 (6) percentages Other 3 (16) 1 (6) Flexitouch system, HCPCS E0652 Affected arm 0.724 Bio Compression 2004 Sequen- Left 13 (72) 11 (61) tial Circulator, HCPCS E0651 Right 5 (23) 7 (39) p-value based on Mann–Whit- Surgery on dominant side 5 (28) 7 (39) 0.725 ney test 3282 Support Care Cancer (2012) 20:3279–3286 measurement, the end of the tensioning mechanism is pulled provided the subject with specific instructions to ensure until the calibration point, a silver disk separated by two thorough understanding of the operation of the device to colored beads, is seen. Girth measurements were done with which they were assigned. Subjects were reminded to con- subjects seated and their arms extended in front of them with tinue the other components of their home care including their palm resting on their ipsilateral knee. Girths were exercise, skin care, and compression garment use as previ- measured at 4-cm intervals starting at the ulnar styloid and ously recommended by their clinician. Subjects were also ending at the last full 4-cm interval near the axilla. Girth instructed to complete the daily usage log pertaining to the measurements were taken primarily by one person at each of the assigned device and to document treatment compliance and three sites. These individuals were all experienced lymphedema were instructed on the treatment protocol. therapists who routinely perform these measurements daily in their active lymphedema practice. The girth values served as Treatment protocol inputs to a software algorithm that calculates arm volume based on a standardized and validated frustum model [30–33]. Abso- The assigned PCD was used for home treatment 1 h/day in lute arm volumes of affected arms (VA) and contralateral arms addition to existing routine care, which included compres- (VC) at week 0 and week 12 were determined from these girth sion garment wear for 23 h per day. The SPCD consists of a measurements. Edema volumes in milliliters (EVOL) were cal- gradient, sequential pneumatic compressor weighing 6 lbs culated as (VA−VC) and percentage edema volume (%EVOL) with dimensions of 5.5″×12″×8″. It can be set within a was calculated as 100(VA−VC) / VC. pressure range of 0–125 mmHg. The compressor unit attaches to an arm garment with four compression chambers Local tissue water ranging from approximately 15 to 24 cm wide depending on garment size. Chambers inflate sequentially at a rate of 18 s/ An index of local skin tissue water was measured using the chamber until all chambers are fully inflated for a total tissue dielectric constant (TDC) method [34, 35]. The TDC inflation time of approximately 72 s. Full garment inflation is the electrical dielectric constant or permittivity of the is then held for 22 s before all chambers simultaneously tissue and is expressed relative to the permittivity of a deflate for 18 s. Garments have zipper closures and are vacuum, so it is a dimensionless number. Its measured value made of 200 denier nylon-coated Oxford with 3 mils of depends on the amount of water within the measurement polyurethane. The SPCD was set according to the manufac- volume; pure water has a value of about 78. With the probe turer’s suggested setting of 30 mmHg. and frequency used (300 MHz), the TDC value reflects both The APCD consists of an electronic controller that attaches free and bound water within the measurement volume to a to three garments that treat the full upper extremity, which skin depth of about 2.5 mm. TDC values were obtained at includes the arm, adjacent chest, and truncal quadrant. The weeks 0 and 12 using a commercial device (MoistureMeter- controller unit weighs 8 lbs with dimensions of 10.4″×9.8″× D, Delfin Technologies, Ltd., Kuopio, Finland). TDC meas- 4.7″. The garment set contains 26–28 (depending on garment urements were made on both anterior forearms at a stan- size) narrow, curved chambers ranging from 3.8 to 4.4 cm dardized site along the forearm midline located 8 cm distal wide which wrap around to follow the contours of the limb to the antecubital crease. Triplicate measurements at each and trunk and close with hook and loop fasteners. The outer site were obtained by placing the probe in contact with the fabric of the garment is made of 100% nylon and is latex free. skin and held in position using gentle pressure. These trip- The inflation/deflation cycle for each chamber is 1–3sin licate measurements were averaged to produce a single duration. No two chambers are fully inflated simultaneously. value for each site. These measurements were made in 28 The APCD system has 13 therapy program options and subjects (14 subjects in the APCD group and in 14 subjects applies light, variable pressure to the trunk and the affected in SPCD group) all coming from a single center, Healing arm using multichambered, inflatable, and stretchable fabric Hands of Lymphatics (Hallandale Beach, FL), per protocol. garments. The APCD was set to the full upper extremity Measurements were made at week 0 prior to the start of program (UE01) at the device’s standard pressure setting treatment and at week 12 at the end of treatment. This according to the manufacturer’s suggested settings. Published method for assessment has been extensively used to assess data indicates that this standard setting applies between 9.0± localized skin water and its change [34–38]. 4.2 mmHg and 13.7±4.8 mmHg to the forearm during the standard treatment program [39]. Protocol and procedures Data analysis After consent and randomization, subjects were seen in the clinic for their baseline (week 0) measurements. Each sub- The goal of the main study analysis was to evaluate possible ject was seen and examined by a study clinician who differential effects of device treatment on edema volume and Support Care Cancer (2012) 20:3279–3286 3283 local tissue water. Possible differences between devices control arm. This is consistent with a significant device were assessed using a general linear model (GLM) for treatment effect characterized by a week 0 to week 12 repeated measures (SPSS v13) with week (week 12 vs. week edema volume change of −118±170 ml for the advanced 0) as the within-subject repeated measure and device (stan- group and +6.3±216 ml change for the standard group. dard or advanced) as the between-subjects factor. The sig- Figure 1 is a box plot showing these changes in edema nificance level for the acceptance of a device effect was a volume from week 0 to week 12. Negative values denote priori set to a p value of 0.05 as determined for device–week reductions in edema volume. These absolute changes corre- interaction. The edema volume analysis included 18 sub- spond to changes in percentage edema volume of −29±44% jects in the APCD group and 18 in the SPCD group. The for the advanced group vs. +16±63% for the standard (p0 local tissue water analysis included 14 subjects in each 0.018). Repeated measures analysis also showed a signifi- group. Possible differences in parameters between groups cant group by week interaction for the affected arm TDC or differences between arms at week 0 and week 12 were value with the advanced group demonstrating a reduction in separately tested using t tests for independent samples. TDC of −3.1±4.9 as compared to +0.4±3.9 for the standard Additional endpoints that were evaluated were the num- group (p00.05). These absolute values correspond to a ber/severity of adverse events. Primary safety endpoints mean reduction in TDC value of 5.8% for the advanced included any signs or symptoms of acute infection or other group and a 1.9% increase for standard group. adverse clinical event defined as any symptom, sign, illness, Device compliance was very good in both groups with or experience that developed or worsened in severity during the APCD group completing a total of 1,434 treatments out the course of the study. Serious adverse events were defined of 1,512 (95%) and the SPCD group completing 1,494 out as an event that is fatal, life threatening, requires hospitali- of 1,512 (99%). Per patient report, compliance with the zation, or if left untreated could lead to persistent disability. other home treatment components between the groups was very similar, with the biggest difference in exercise. In both groups, 78% (14 per group) reported compliance with daily Results compression garment wear with 22% (four per group) reporting partial compliance defined as garment wear less Arm volumes, edema volumes, and tissue water results are than 3 days/week or only during the night. Likewise, the given as mean ± standard deviation and summarized in same number in each group, 14 (67%), reported performing Table 2. At baseline (week 0), there were no significant self-massage daily or almost daily, with 33% or six in each between-group differences in affected or control arm vol- group reporting infrequent compliance with daily self- umes, edema volume, or TDC values of affected or control massage. Compliance with skin care was high and equal in both groups with 94% (17) in each group reporting daily arms. Contrastingly, and as expected, affected arms had significantly greater TDC values than control arms indicat- compliance. Regarding exercise, 83% (15) of the SPCD group reported daily exercise compared to 61% (11) in the ing greater skin tissue water of the affected arm. The GLM repeated measures analysis showed a significant group by APCD group. It is important to note that subjects were week interaction for both edema volume and for affected instructed to continue with all other home treatment compo- arm TDC values but no interaction for TDC values of the nents they were doing prior to starting this study. Table 2 Volume and TDC result summary Group Week 0 Week 12 Week by group a a APCD SPCD p value APCD SPCD p value Affected arm volume (ml) 3,102±755 3,104±966 0.994 2,952±724 3,013±773 0.645 0.141 Control arm volume (ml) 2,546±657 2,573±695 0.902 2,514±599 2,537±631 0.912 0.942 Edema volume (ml) 556±318 531±372 0.823 438±344 537±293 0.363 0.050 Percent edema volume (%) 23.0±13.9 19.9±11.9 0.471 18.2±14.0 21.0±10.7 0.571 0.047 TDC of affected arm 36.9±9.8 33.2±7.8 0.260 33.8±7.6 33.5±6.6 0.904 0.049 TDC of control arm 26.2±3.8 25.3±3.6 0.502 25.6±2.4 25.8±3.8 0.907 0.510 Data are mean ± standard deviation. Volume data based on 18 per group, and TDC data based on 14 per group As determined by independent t tests between groups Significance of week by group interaction Statistically significant 3284 Support Care Cancer (2012) 20:3279–3286 Fig. 1 Changes in edema volume from week 0 to week 12 (box plot). Circles and star indicate possible outliers Seven adverse events were recorded that were classified The SPCD utilizes a slower inflation/deflation cycle as “unlikely,”“possibly,” or “definitely” device-related: one wherein the garment takes approximately 72 s to fully in the APCD group and six in the SPCD group. Five were inflate; inflation is held for 22 s and then the air is released further classified as “serious” and one “nonserious”. Table 3 from all chambers simultaneously. This process results in provides the descriptions of these adverse events. application of a static pressure to the full arm at a level likely above that which would compress lymphatic capillaries and thereby prevent lymph uptake during this interval [40–42]. The APCD utilizes a faster treatment cycle whereby each Discussion chamber inflates/deflates in 1–3 s before the next chamber inflates. This faster and more succinct cycle of pressure and The results of this pilot study suggest that application of release approximates those techniques applied with MLD the APCD for the home maintenance phase of lymphe- [11] and would be consistent with a pressure profile that has dema secondary to breast cancer treatment provides better been described to increase lymph drainage [11, 39]. The outcomes as judged by the significant arm edema and resulting dynamic and variable pressures likely induce the tissue water reductions for the APCD as compared to the initial lymph capillaries to respond to the pressure changes SPCD with fewer complications. Because baseline subject occurring in the skin. Furthermore, the more rapidly chang- characteristics were similar between groups and treatment ing pressure waves may better facilitate lymph drainage time and compliance to treatment was essentially the because this timing better corresponds to the timing of same, we suggest that the outcome differences may be arterial and respiratory pulses, which are thought to stimu- associated with differences between device function and late lymphatics [11, 43, 44]. treatment area. Table 3 Description of adverse events that might be device-related for advanced and standard PCD groups (APCD, SPCD) Description Group Device-related Category Rash on arm SPCD Unlikely Nonserious Increased arm swelling SPCD Possibly Serious Breast inflammation; increased swelling and pain; developed infection and fibrosis SPCD Possibly Serious Increased hand swelling SPCD Definitely Serious Pain in forearm and numbness in fingers SPCD Definitely Nonserious Increased swelling of hand and torso; pain in axilla and back SPCD Definitely Serious Increased swelling of lymph nodes in contralateral axilla APCD Possibly Serious Support Care Cancer (2012) 20:3279–3286 3285 In addition, the garments of the APCD studied here References provide specific directional movement that covers more of the affected region than does the SPCD, therefore treating 1. 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A randomized controlled trial comparing two types of pneumatic compression for breast cancer-related lymphedema treatment in the home

Supportive Care in Cancer , Volume 20 (12) – May 2, 2012

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Pubmed Central
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© The Author(s) 2012
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0941-4355
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1433-7339
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10.1007/s00520-012-1455-2
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Abstract

Support Care Cancer (2012) 20:3279–3286 DOI 10.1007/s00520-012-1455-2 ORIGINAL ARTICLE A randomized controlled trial comparing two types of pneumatic compression for breast cancer-related lymphedema treatment in the home Caroline E. Fife & Suzanne Davey & Erik A. Maus & Renie Guilliod & Harvey N. Mayrovitz Received: 21 November 2011 /Accepted: 26 March 2012 /Published online: 2 May 2012 The Author(s) 2012. This article is published with open access at Springerlink.com Abstract calculations, and tissue water was determined based on meas- Purpose Pneumatic compression devices (PCDs) are used urements of the arm tissue dielectric constant (TDC). in the home setting as adjunctive treatment for lymphedema Results The APCD-treated group experienced an average of after acute treatment in a clinical setting. PCDs range in 29% reduction in edema compared to a 16% increase in the complexity from simple to technologically advanced. The SPCD group. Mean changes in TDC values were a 5.8% objective of this prospective, randomized study was to deter- reduction for the APCD group and a 1.9% increase for the mine whether an advanced PCD (APCD) provides better out- SPCD group. Conclusion This study suggests that for the home mainte- comes as measured by arm edema and tissue water reductions compared to a standard PCD (SPCD) in patients with arm nance phase of treatment of arm lymphedema secondary to breast cancer therapy, the adjuvant treatment with an APCD lymphedema after breast cancer treatment. Methods Subjects were randomized to an APCD (Flexi- provides better outcomes than with a SPCD. touch system, HCPCS E0652) or SPCD (Bio Compression . . 2004, HCPCS E0651) used for home treatment 1 h/day for Keywords Lymphedema Pneumatic compression devices . . 12 weeks. Pressure settings were 30 mmHg for the SPCD Breast cancer Manual lymphatic drainage Flexitouch® and upper extremity treatment program (UE01) with stan- system Bio compression 2004 sequential circulator dard pressure for the APCD. Thirty-six subjects (18 per group) with unilateral upper extremity lymphedema with at least 5% arm edema volume at the time of enrollment, com- Introduction pleted treatments over the 12-week period. Arm volumes were determined from arm girth measurements and suitable model Lymphedema is a condition resulting from lymphatic dys- function in which persistent swelling exists due to an ab- normal accumulation of protein-rich fluid in an extremity or other body region and is accompanied by marked subcuta- : : C. E. Fife (*) E. A. Maus R. Guilliod neous and skin changes as the condition worsens [1]. Pri- Department of Internal Medicine, Division of Cardiology, mary lymphedema is caused by the abnormal development University of Texas Health Science Center, Memorial Hermann of the lymphatic system and may present at birth, during late Center for Wound Care and Lymphedema Management, 6431 Fannin, MSB 1.247, adolescence, or in early adulthood. Secondary lymphedema Houston, TX 77030, USA results from extrinsic damage or obstruction of the lym- e-mail: Caroline.E.Fife@uth.tmc.edu phatics. In developed countries, breast cancer treatment is recognized as the major cause of secondary lymphedema S. Davey Healing Hands of Lymphatics, [1–3]. The incidence of breast cancer-related lymphedema Hallandale Beach, FL, USA rises dramatically from 3 to 15% after sentinel node biopsy, to 10–20% after complete axillary dissection, and 30 to 50% H. N. Mayrovitz with subsequent radiotherapy [4–7]. Recent data obtained College of Medical Sciences, Nova Southeastern University, from fluorescent lymphatic imaging suggests that some Ft. Lauderdale, FL, USA 3280 Support Care Cancer (2012) 20:3279–3286 patients developing secondary lymphedema may have had a for long-term, as treatment durations ranged from 2 to genetic predisposition to lymphatic malfunction [8, 9]. Cur- 6 hours daily [26] and/or were limited to lower extremity rently, no cure exists for lymphedema, so treatment aims to lymphedema [19, 24]. One comparative study has been ameliorate the swelling, lessen its severity and symptoms, conducted to date regarding APCDs. A pilot RCT investi- and impede progression. Effective long-term treatment strat- gated the home maintenance phase of ten patients who had egies are, therefore, crucial. unilateral breast cancer-associated lymphedema of the arm The traditional initial treatment for lymphedema is com- by comparing self-MLD with an APCD for 1 h each day for plete decongestive therapy (CDT), which consists of manual 14 days followed by crossover to the other treatment with a lymphatic drainage (MLD), short-stretch compression ban- 1-week washout period before each treatment [27]. Post- daging, decongestive exercises, and skin care [10]. While treatment arm volume and patients’ mean weight signifi- this regimen works effectively for most patients when they cantly decreased after using the APCD but not after self- are treated in a clinical setting by a well-qualified therapist, administered MLD [27]. ultimately it is necessary for the patient to attempt to main- Despite development of some clinical consensus that tain the gains and manage this life-long condition in a home APCDs may yield better outcomes for some patients than setting. Successful transfer to the home care setting is chal- simple PCDs [28, 29], further published evidence is lacking. lenging. Many patients find the procedures, particularly Based on the theoretical advantages potentially offered by those for self-MLD and bandaging, time-consuming and an APCD as supported by prior literature, we hypothesized difficult to carry out, especially if they have physical limi- that an APCD would result in better outcomes than less tations from comorbidities. Poor patient adherence to pre- advanced systems when used in the home environment. scribed home treatments can result in failure to maintain The specific goal of this study was to test this hypothesis progress and may likely negate gains achieved during pre- by evaluating and comparing changes in arm edema volume vious clinical treatments. and local tissue water content achieved with the use of either One treatment adjunct that may aid the patient in the an APCD or standard PCD (SPCD) system. home management setting is use of pneumatic compression devices (PCDs). PCDs utilize an air compressor unit that attaches to a garment or series of garments. The garment Materials and methods chambers sequentially inflate and deflate applying pressure against the skin thereby creating a treatment effect. PCDs This study was a prospective, randomized controlled trial in range from simple single-chamber or multichamber devices which patients were consented and randomized in a 1:1 ratio with limited adjustability, to advanced devices with more to either a SPCD (Bio Compression 2004 Sequential Circu- garment options and a wide array of treatment options and lator PCD, Bio Compression Systems, Moonachie NJ, adjustability to address different clinical needs such as fi- USA) or an APCD (Flexitouch system, Tactile Systems brosis, truncal swelling, chronic wounds, or localized swell- Technology, Inc., Minneapolis MN, USA). Each device ing. The adjustability and expanded programs available with was to be used for the home maintenance phase of treatment many advanced PCDs (APCDs) provide for faster and more for secondary upper extremity lymphedema caused by succinct cycles of pressure and relaxation with compression breast cancer treatment. levels better approximating those applied with MLD [11]. Three centers participated in this study: Healing Hands of Some APCDs provide specific garments enabling truncal Lymphatics (Hallandale Beach, FL, USA), Washington treatment, which is deemed fundamental in clinical training Hospital Healthcare System (Fremont, CA, USA), and Me- in MLD technique and is based on lymphatic architecture morial Hermann Hospital (Texas Medical Center, Houston, and animal experimental evidence [11–14]. TX, USA). The trial was approved by the following institu- Validation of treatment and outcome advantages associ- tional review boards (IRBs): Sterling IRB (3139, 02-16- ated with advanced devices in comparison to standard devi- 2009), Washington Hospital Healthcare System IRB (02- ces is lacking. Although, several studies have reported 19-2009), and University of Texas IRB (HSC-MS-10- positive results with use of PCD treatment [15–25], it is 0050, 03-05-2009). This study was conducted in accordance difficult to compare outcomes from the initial body of with US and international good clinical practices (FDA Title evidence regarding early PCDs with more current APCD 21, part 812 and International Conference on Harmonization options. Many of these studies are over 10 years old and guidelines), applicable government regulations and institu- lack sufficient detail about the devices studied to enable tional research policies and procedures. Subjects who were comparisons to aid in device selection or treatment protocol recruited from the participating lymphedema treatment cen- with regard to currently marketed devices, especially the ters had either previously sought or were currently seeking newer PCD technologies [26]. Of significance, most of the treatment for their lymphedema. A total of 36 patients treatment protocols studied were not practical or sustainable (equally divided between standard and APCD use) form Support Care Cancer (2012) 20:3279–3286 3281 the basis of the present report. These 36 patients were fully Tests for baseline group differences in age and BMI, evaluated for edema volume changes after 12 weeks of in- number of nodes that were removed during the subjects’ home treatment and 28 of these patients (also equally divid- initial surgery as well as time between surgery and study ed) were evaluated for changes in arm tissue water content. start showed no significant difference as evaluated via inde- pendent t tests (Table 1). Tests for normality of the data for Eligibility the number of nodes that were removed during the subjects’ initial surgery as well as time between surgery and study Subjects had to be at least 18 years old and able to give start (Shapiro–Wilk test) indicated non-normality (p< informed consent. A confirmed diagnosis of upper extremity 0.001), so this data was tested using the Mann–Whitney lymphedema secondary to breast cancer treatment was test. Results (Table 1) show insignificant differences in both required, and each patient had to have previously completed parameters between groups. Further, tests for baseline group intensive lymphedema treatment (phase I) and discharged to differences in race, affected arm side, dominant arm side, home maintenance (phase II) but the patient must not have type of surgery, radiation treatment, and chemotherapy also received in-home PCD therapy for the past 3 months. Fur- showed no significant difference as evaluated via Pearson’s ther, at least 5% edema volume needed to be present at the Chi Square analyses (Table 1). Thus, with respect to these time of study enrollment. demographic variables, the two groups were well balanced at entry into the study. Baseline data Arm girth measurements Demographic information including age, gender, race, arm dominance, and BMI was collected at baseline. Medical Arm circumferences (girths) were measured with a Gulick II history data collected included type of surgery, chemother- tape measure. The Gulick II tape measure (model 67020; apy, radiation, time since surgery, and number of nodes Country Technology, Inc., Gay Mills, WI) has a tension removed, if applicable. Table 1 summarizes these data for meter attached, so that the tape’s tension can be standardized all subjects separated by randomly assigned groups (SPCD during measurement. The no-stretch, retractable tape is cal- vs. APCD). ibrated to indicate precisely a 4-once tension. During Table 1 Baseline comparison of a b Characteristic APCD (n018) SPCD (n018) p value the advanced and standard PCD groups (APCD, SPCD) Age 63.9±12.2 59.7±12.6 0.315 BMI 28.2±4.6 30.6±7.4 0.258 Months between surgery and study start 105.9±119.7 75.4±73.4 0.815 Number of nodes removed 11.9±8.7 12.6±11.2 0.987 Surgery type 0.441 Mastectomy 12 (67) 15 (83) Lumpectomy 6 (33) 3 (17) Radiation therapy 0.717 Yes 12 (67) 13 (72) No 6 (33) 5 (28) Chemotherapy 0.675 Yes 15 (83) 14 (78) No 3 (17) 4 (22) Race 0.725 Caucasian 10 (56) 13 (72) African American 3 (17) 3 (17) Numbers in parentheses are Hispanic 2 (11) 1 (6) percentages Other 3 (16) 1 (6) Flexitouch system, HCPCS E0652 Affected arm 0.724 Bio Compression 2004 Sequen- Left 13 (72) 11 (61) tial Circulator, HCPCS E0651 Right 5 (23) 7 (39) p-value based on Mann–Whit- Surgery on dominant side 5 (28) 7 (39) 0.725 ney test 3282 Support Care Cancer (2012) 20:3279–3286 measurement, the end of the tensioning mechanism is pulled provided the subject with specific instructions to ensure until the calibration point, a silver disk separated by two thorough understanding of the operation of the device to colored beads, is seen. Girth measurements were done with which they were assigned. Subjects were reminded to con- subjects seated and their arms extended in front of them with tinue the other components of their home care including their palm resting on their ipsilateral knee. Girths were exercise, skin care, and compression garment use as previ- measured at 4-cm intervals starting at the ulnar styloid and ously recommended by their clinician. Subjects were also ending at the last full 4-cm interval near the axilla. Girth instructed to complete the daily usage log pertaining to the measurements were taken primarily by one person at each of the assigned device and to document treatment compliance and three sites. These individuals were all experienced lymphedema were instructed on the treatment protocol. therapists who routinely perform these measurements daily in their active lymphedema practice. The girth values served as Treatment protocol inputs to a software algorithm that calculates arm volume based on a standardized and validated frustum model [30–33]. Abso- The assigned PCD was used for home treatment 1 h/day in lute arm volumes of affected arms (VA) and contralateral arms addition to existing routine care, which included compres- (VC) at week 0 and week 12 were determined from these girth sion garment wear for 23 h per day. The SPCD consists of a measurements. Edema volumes in milliliters (EVOL) were cal- gradient, sequential pneumatic compressor weighing 6 lbs culated as (VA−VC) and percentage edema volume (%EVOL) with dimensions of 5.5″×12″×8″. It can be set within a was calculated as 100(VA−VC) / VC. pressure range of 0–125 mmHg. The compressor unit attaches to an arm garment with four compression chambers Local tissue water ranging from approximately 15 to 24 cm wide depending on garment size. Chambers inflate sequentially at a rate of 18 s/ An index of local skin tissue water was measured using the chamber until all chambers are fully inflated for a total tissue dielectric constant (TDC) method [34, 35]. The TDC inflation time of approximately 72 s. Full garment inflation is the electrical dielectric constant or permittivity of the is then held for 22 s before all chambers simultaneously tissue and is expressed relative to the permittivity of a deflate for 18 s. Garments have zipper closures and are vacuum, so it is a dimensionless number. Its measured value made of 200 denier nylon-coated Oxford with 3 mils of depends on the amount of water within the measurement polyurethane. The SPCD was set according to the manufac- volume; pure water has a value of about 78. With the probe turer’s suggested setting of 30 mmHg. and frequency used (300 MHz), the TDC value reflects both The APCD consists of an electronic controller that attaches free and bound water within the measurement volume to a to three garments that treat the full upper extremity, which skin depth of about 2.5 mm. TDC values were obtained at includes the arm, adjacent chest, and truncal quadrant. The weeks 0 and 12 using a commercial device (MoistureMeter- controller unit weighs 8 lbs with dimensions of 10.4″×9.8″× D, Delfin Technologies, Ltd., Kuopio, Finland). TDC meas- 4.7″. The garment set contains 26–28 (depending on garment urements were made on both anterior forearms at a stan- size) narrow, curved chambers ranging from 3.8 to 4.4 cm dardized site along the forearm midline located 8 cm distal wide which wrap around to follow the contours of the limb to the antecubital crease. Triplicate measurements at each and trunk and close with hook and loop fasteners. The outer site were obtained by placing the probe in contact with the fabric of the garment is made of 100% nylon and is latex free. skin and held in position using gentle pressure. These trip- The inflation/deflation cycle for each chamber is 1–3sin licate measurements were averaged to produce a single duration. No two chambers are fully inflated simultaneously. value for each site. These measurements were made in 28 The APCD system has 13 therapy program options and subjects (14 subjects in the APCD group and in 14 subjects applies light, variable pressure to the trunk and the affected in SPCD group) all coming from a single center, Healing arm using multichambered, inflatable, and stretchable fabric Hands of Lymphatics (Hallandale Beach, FL), per protocol. garments. The APCD was set to the full upper extremity Measurements were made at week 0 prior to the start of program (UE01) at the device’s standard pressure setting treatment and at week 12 at the end of treatment. This according to the manufacturer’s suggested settings. Published method for assessment has been extensively used to assess data indicates that this standard setting applies between 9.0± localized skin water and its change [34–38]. 4.2 mmHg and 13.7±4.8 mmHg to the forearm during the standard treatment program [39]. Protocol and procedures Data analysis After consent and randomization, subjects were seen in the clinic for their baseline (week 0) measurements. Each sub- The goal of the main study analysis was to evaluate possible ject was seen and examined by a study clinician who differential effects of device treatment on edema volume and Support Care Cancer (2012) 20:3279–3286 3283 local tissue water. Possible differences between devices control arm. This is consistent with a significant device were assessed using a general linear model (GLM) for treatment effect characterized by a week 0 to week 12 repeated measures (SPSS v13) with week (week 12 vs. week edema volume change of −118±170 ml for the advanced 0) as the within-subject repeated measure and device (stan- group and +6.3±216 ml change for the standard group. dard or advanced) as the between-subjects factor. The sig- Figure 1 is a box plot showing these changes in edema nificance level for the acceptance of a device effect was a volume from week 0 to week 12. Negative values denote priori set to a p value of 0.05 as determined for device–week reductions in edema volume. These absolute changes corre- interaction. The edema volume analysis included 18 sub- spond to changes in percentage edema volume of −29±44% jects in the APCD group and 18 in the SPCD group. The for the advanced group vs. +16±63% for the standard (p0 local tissue water analysis included 14 subjects in each 0.018). Repeated measures analysis also showed a signifi- group. Possible differences in parameters between groups cant group by week interaction for the affected arm TDC or differences between arms at week 0 and week 12 were value with the advanced group demonstrating a reduction in separately tested using t tests for independent samples. TDC of −3.1±4.9 as compared to +0.4±3.9 for the standard Additional endpoints that were evaluated were the num- group (p00.05). These absolute values correspond to a ber/severity of adverse events. Primary safety endpoints mean reduction in TDC value of 5.8% for the advanced included any signs or symptoms of acute infection or other group and a 1.9% increase for standard group. adverse clinical event defined as any symptom, sign, illness, Device compliance was very good in both groups with or experience that developed or worsened in severity during the APCD group completing a total of 1,434 treatments out the course of the study. Serious adverse events were defined of 1,512 (95%) and the SPCD group completing 1,494 out as an event that is fatal, life threatening, requires hospitali- of 1,512 (99%). Per patient report, compliance with the zation, or if left untreated could lead to persistent disability. other home treatment components between the groups was very similar, with the biggest difference in exercise. In both groups, 78% (14 per group) reported compliance with daily Results compression garment wear with 22% (four per group) reporting partial compliance defined as garment wear less Arm volumes, edema volumes, and tissue water results are than 3 days/week or only during the night. Likewise, the given as mean ± standard deviation and summarized in same number in each group, 14 (67%), reported performing Table 2. At baseline (week 0), there were no significant self-massage daily or almost daily, with 33% or six in each between-group differences in affected or control arm vol- group reporting infrequent compliance with daily self- umes, edema volume, or TDC values of affected or control massage. Compliance with skin care was high and equal in both groups with 94% (17) in each group reporting daily arms. Contrastingly, and as expected, affected arms had significantly greater TDC values than control arms indicat- compliance. Regarding exercise, 83% (15) of the SPCD group reported daily exercise compared to 61% (11) in the ing greater skin tissue water of the affected arm. The GLM repeated measures analysis showed a significant group by APCD group. It is important to note that subjects were week interaction for both edema volume and for affected instructed to continue with all other home treatment compo- arm TDC values but no interaction for TDC values of the nents they were doing prior to starting this study. Table 2 Volume and TDC result summary Group Week 0 Week 12 Week by group a a APCD SPCD p value APCD SPCD p value Affected arm volume (ml) 3,102±755 3,104±966 0.994 2,952±724 3,013±773 0.645 0.141 Control arm volume (ml) 2,546±657 2,573±695 0.902 2,514±599 2,537±631 0.912 0.942 Edema volume (ml) 556±318 531±372 0.823 438±344 537±293 0.363 0.050 Percent edema volume (%) 23.0±13.9 19.9±11.9 0.471 18.2±14.0 21.0±10.7 0.571 0.047 TDC of affected arm 36.9±9.8 33.2±7.8 0.260 33.8±7.6 33.5±6.6 0.904 0.049 TDC of control arm 26.2±3.8 25.3±3.6 0.502 25.6±2.4 25.8±3.8 0.907 0.510 Data are mean ± standard deviation. Volume data based on 18 per group, and TDC data based on 14 per group As determined by independent t tests between groups Significance of week by group interaction Statistically significant 3284 Support Care Cancer (2012) 20:3279–3286 Fig. 1 Changes in edema volume from week 0 to week 12 (box plot). Circles and star indicate possible outliers Seven adverse events were recorded that were classified The SPCD utilizes a slower inflation/deflation cycle as “unlikely,”“possibly,” or “definitely” device-related: one wherein the garment takes approximately 72 s to fully in the APCD group and six in the SPCD group. Five were inflate; inflation is held for 22 s and then the air is released further classified as “serious” and one “nonserious”. Table 3 from all chambers simultaneously. This process results in provides the descriptions of these adverse events. application of a static pressure to the full arm at a level likely above that which would compress lymphatic capillaries and thereby prevent lymph uptake during this interval [40–42]. The APCD utilizes a faster treatment cycle whereby each Discussion chamber inflates/deflates in 1–3 s before the next chamber inflates. This faster and more succinct cycle of pressure and The results of this pilot study suggest that application of release approximates those techniques applied with MLD the APCD for the home maintenance phase of lymphe- [11] and would be consistent with a pressure profile that has dema secondary to breast cancer treatment provides better been described to increase lymph drainage [11, 39]. The outcomes as judged by the significant arm edema and resulting dynamic and variable pressures likely induce the tissue water reductions for the APCD as compared to the initial lymph capillaries to respond to the pressure changes SPCD with fewer complications. Because baseline subject occurring in the skin. Furthermore, the more rapidly chang- characteristics were similar between groups and treatment ing pressure waves may better facilitate lymph drainage time and compliance to treatment was essentially the because this timing better corresponds to the timing of same, we suggest that the outcome differences may be arterial and respiratory pulses, which are thought to stimu- associated with differences between device function and late lymphatics [11, 43, 44]. treatment area. Table 3 Description of adverse events that might be device-related for advanced and standard PCD groups (APCD, SPCD) Description Group Device-related Category Rash on arm SPCD Unlikely Nonserious Increased arm swelling SPCD Possibly Serious Breast inflammation; increased swelling and pain; developed infection and fibrosis SPCD Possibly Serious Increased hand swelling SPCD Definitely Serious Pain in forearm and numbness in fingers SPCD Definitely Nonserious Increased swelling of hand and torso; pain in axilla and back SPCD Definitely Serious Increased swelling of lymph nodes in contralateral axilla APCD Possibly Serious Support Care Cancer (2012) 20:3279–3286 3285 In addition, the garments of the APCD studied here References provide specific directional movement that covers more of the affected region than does the SPCD, therefore treating 1. 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Supportive Care in CancerPubmed Central

Published: May 2, 2012

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