Evidence-Based Practice Guideline for the Management of Lymphedema Proposed by the Japanese Lymphedema Society

Abstract

Background:

Secondary lymphedema mostly occurs as an aftereffect of cancer treatment, and it is estimated that 100,000–150,000 patients are affected in Japan. An estimated 3500 patients, develop lymphedema of the lower and upper extremities each year secondary to uterine and breast cancer treatment. Medical reimbursement was first instituted in April 2008 by the Ministry of Health, Labour and Welfare in Japan. Since 2008, we have developed guidelines regarding treatment options for patients with lymphedema based on scientific evidence. This is the third edition of the guidelines established by the Japanese Lymphedema Society (JLES), published in 2018. The JLES Practice Guideline-Making Committee (PGMC) developed 21 clinical questions (CQs).

Methods and Results:

A review of these 15 CQs was performed in accordance with the methodology for establishing clinical guidelines. The 15 recommendations for each of these CQs were developed and discussed until consensus by the PGMC was reached. Moreover, outside members who had no involvement in these guidelines evaluated the contents using the Appraisal of Guidelines for Research and Evaluation (AGREE) II reporting checklist.

Conclusion:

These guidelines have been produced for the adequate management of lymphedema by doctors and other medical staff on the lymphedema management team of medical institutes, including nurses, physical technicians, and occupational therapists.

Introduction

In Japan, lymphedema mostly occurs as an aftereffect of cancer treatment. Reimbursement for lymphedema self-management was first instituted in 2008. Since then, postoperative instruction for the prevention of lymphedema at the time of hospitalization has been covered by insurance, including prophylactic self-care coaching and use of compression garments for patients with breast, gynecological, and prostate cancer, among others. Re-instruction charges were calculated in the Outpatient Department in 2010.

Since 2016, complex decongestive therapy (CDT), including multilayer lymphedema bandaging (MLLB) and manual lymph drainage (MLD), has been comprehensively included.

In accordance with progression of reimbursement for lymphedema management, the guideline has been updated. The first edition of these practice guidelines was produced in 2010, with a second edition published in 2014 by the Japanese Lymphedema Society (JLES).

We at JLES aim to share accurate and recent knowledge on the basis of scientific evidence to assist patients in making effective treatment decisions.

Clinical Practice of Lymphedema in Japan

The diagnosis of secondary lymphedema is based on the diagnostic criteria of the International Society of Lymphology (ISL), but the lymph scintigraphy recommended by ISL is not covered by insurance in Japan and is not used in general practice.

For the diagnosis of primary lymphedema, the St George's algorithm has revealed where new genes have been discovered and that a molecular diagnosis was possible in 26% of all patients overall and 41% of those tested.¹ However, molecular diagnostics are not yet widespread in Japan.

In addition, bioimpedance spectroscopy, for which evidence has been accumulated in recent years, is not covered by insurance in Japan. The diagnosis of lymphedema is based on history-taking, inspection, palpation by a clinician, and measurement of the extremities using a tape measure in the clinical setting. The use of ISL classification, which is recommended for lymphedema staging by the JLES, varies in clinical practice. Additionally, the JLES offers a technical educational training program to medical and co-medical staff for the evaluation of lymphedema. According to the ISL,¹ lymphedema is classified into four stages. Specifically, stage 0 lymphedema (also termed as subclinical or latent) is defined as no visible changes to the arm, hand, or upper body, although there might be difference in feeling, such as mild tingling, unusual tiredness, or slight heaviness. Stage 0 lymphedema might be present for months or years before the development of obvious symptoms. In stage 1, that is, mild lymphedema, the arm, hand, trunk, breast, or other areas appear mildly swollen as the protein-rich fluid starts to accumulate. Applying pressure on the skin creates a temporary small dent or pit; this is occasionally referred to as pitting edema. This early-stage lymphedema is considered reversible with treatment because the skin and tissues are not permanently damaged. For instance, the swelling resolves with elevation of the affected area. In stage 2, that is, moderate lymphedema, the swelling is worse and does not resolve by elevating the affected area; furthermore, applying pressure on the skin does not leave a pit; this type is referred to as non-pitting edema. Some of the changes to the tissue under the skin include inflammation, hardening, and thickening. Stage 2 lymphedema can be managed with treatment; however, the tissue damage is irreversible. Stage 3 or severe lymphedema is the most advanced presentation, yet relatively rare in patients with breast cancer. At this stage, the affected limb or area becomes markedly enlarged and misshapen, and the skin takes on a leathery wrinkled appearance.

Guideline Development Process

The guideline-making process was governed by the Medical Information Network Distribution System (Minds) “Minds Handbook for Clinical Practice Guideline Development.”²

Definition of Recommendation Grade

A: Strongly recommended (more than one randomized controlled trial [RCT] with the same outcomes)

B: Recommended (strong evidence with the same outcomes)

C1: Optional (insufficient evidence)

C2: Not recommended (little evidence)

D: Contraindicated (evidence of adverse effects or morbidity)

Definition of Evidence Grade

Convincing

Probable

Limited-suggestive

Limited-no conclusion

Unlikely

Evaluation of CQs and Recommendations by Experts

The PGMC was composed of five breast surgeons, two gynecologists, one vascular surgeon, and one palliative care specialist. All CQs were evaluated by the committee members using the Delphi method. All CQs and recommendations were deliberated by the experts until 100% consensus was reached.

Evaluation of CQs and Recommendations by Outside Experts

Five outside members, including a doctor, nurse, physical therapist, occupational therapist, and patient (all of whom had no involvement in these guidelines) evaluated the contents using the reporting checklist according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II.³

Practice Guideline for the Management of Lymphedema

CQ1: Self-care for prophylaxis

Recommendation: Grade C1

In Japan, Lymphedema Instruction and Management as well as Lymphedema Combined Treatment have been covered by insurance since 2008 and 2016, respectively.^6,7

Harris et al. cited the following as comprising patient self-care: skin care; coping with wounds, such as stings, clubbed nails, insect bites, pet scratches, and burns; usage of antimicrobial agents for skin infections; warnings regarding saunas, steam baths, and hot baths; travel precautions; exercise recommendations; and weight control. To perform this self-care, it is necessary for patients to receive this information from the medical staff.⁸

Fu et al. examined 136 patients who had received breast cancer treatment. The group that had been given information on lymphedema had significant knowledge regarding the disease, with few symptoms.⁹

CQ2: Sentinel node biopsy

Recommendation: Grade B

The incidence of lymphedema after sentinel lymph node biopsy is ∼1%–11%.^10–12 Although the rate of lymphedema occurrence is clearly lower than that observed in patients with axillary dissection, it may still develop. Given the annual number of patients with breast cancer in Japan (89,100 in 2017), lymphedema care remains important. Medical staff should have basic knowledge regarding lymphedema, and it is desirable to have a medical treatment system in place that can be promptly implemented at the time of onset.

CQ3: Lifestyle factors

Recommendation

Ipsilateral skin infection or cellulitis is “probable.”

Blood collection, injection, and blood pressure measurement on the at-risk arm are “substantial effect on risk unlikely.”

Effect of air travel on the at-risk arm is “substantial effect on risk unlikely,” and for the at-risk leg is “limited-no conclusion.”

Intravenous drip infusion, exposure to extreme temperature, and suntan are “limited-no conclusion.”

Numerous types of studies with various numbers of participants regarding the relationship between lifestyle factors and secondary lymphedema have been conducted.^13–15 Although the relationship between ipsilateral intravenous drip infusion and lymphedema is unclear, chemotherapy in the ipsilateral arm has been associated with secondary lymphedema.¹⁶ Although extreme temperatures and sunbathing have not shown an association with lymphedema, sauna use has been linked to arm edema.¹⁴ Another study revealed a varied risk from sunbathing, depending on the method used to assess the lymphedema.¹⁷

CQ4: Breast reconstruction

Recommendation: substantial effect on risk is unlikely

Whether breast reconstruction after mastectomy induces lymphedema remains unknown. The materials for breast reconstruction include both autologous tissue, such as latissimus muscle and abdominal rectal muscle, and silicone implants. There are four approaches to breast reconstruction: (1) primary one-stage; (2) primary two-stage; (3) secondary one-stage; and (4) secondary two-stage.

Miller et al. focused on the breast reconstruction materials.¹⁸ The multivariate analysis showed that the silicone implant was a safe option for primary two-stage reconstruction (hazard ratio [HR] 0.352, p < 0.0001 vs. HR 0.706, p = 0.2151). Blanchard et al. have shown that the volume of arm lymphedema was significantly reduced following breast reconstruction (p < 0.02) and concluded that two-stage breast reconstruction is suitable for patients with onset of lymphedema (n = 20).¹⁹

We found two studies with a long-term observation period and a large number of patients.^20,21

CQ5: Compression garment

Recommendation

Prevention Upper limbs: Grade C2; lower limbs: Grade C2

Treatment Upper limbs: Grade B; lower limbs: Grade C1

Prevention

A cohort study of 180 patients with breast cancer who had undergone axillary lymph node dissection revealed that early detection and intervention using CDT with a compression garment reduced the incidence of clinical arm lymphedema from 36.4% to 4.4%.²² Two studies with small population sizes demonstrated the prophylactic effect of compression intervention^23,24; however, a randomized study of 80 patients who had undergone inguinal lymph node dissection for melanoma or urogenital cancer found that 6 months of wearing a graduated compression stocking did not decrease the incidence of leg edema.²⁵

Treatment

A meta-analysis of studies on the effect of using a compression garment for arm lymphedema after breast cancer surgery revealed that the standardized mean differences were −0.44 in three randomized studies and −0.26 in three pre- and post-intervention studies.²⁶ A cohort study of 322 patients revealed that the 1-year CDT with a compression garment reduced the relative risk of regaining arm lymphedema volume.²⁷ Several reviews have concluded that there is evidence to support compression therapy, although the studies were often of low quality.^28,29

CQ6: MLD and simple lymph drainage

Recommendation

Prevention

MLD Upper limbs: Recommendation Grade C2; lower limbs: none

Simple lymph drainage (SLD) Upper limbs: none; lower limbs: none

Treatment

MLD Upper and lower limbs: Recommendation Grade C1

SLD Upper and lower limbs: Recommendation Grade C2

Devoogdt et al.³⁰ investigated the preventive effect of MLD on the development of lymphedema related to breast cancer and found only a small effect in the short term. Zimmermann et al.³¹ investigated the efficacy of MLD in preventing secondary lymphedema after breast cancer surgery. Lacomba et al.³² have shown the effectiveness of early physiotherapy, including MLD, massage of scar tissue, and progressive active and action-assisted shoulder exercises in reducing the risk of secondary lymphedema after surgery for breast cancer.

Regarding the role of SLD (which is performed by patients or their caregivers) in prevention, Dönmez and Kapucu³³ recommended using the physical activity program and SLD, along with a follow-up program; however, the sample size of this study was small with no definitive outcomes.

Williams et al.³⁴ reported that MLD significantly reduced excess limb volume. Andersen et al.³⁵ also showed that the addition of MLD to standard therapy could improve treatment outcomes in women with arm lymphedema after breast cancer treatment. Gradalski et al.³⁶ reported that CDT, without the use of MLD and compression bandaging, could be an essential part of lymphedema management. In a recent systematic review and meta-analysis, Shao and Zhong³⁷ reported that the addition of MLD to standard therapy could more effectively manage breast cancer-related lymphedema. Furthermore, Szuba et al.³⁸ showed that CDT in combination with long-term SLD is effective in patients with lymphedema of the extremities.

Liao et al.³⁹ reported the efficacy of intensive multidisciplinary complex decongestive physiotherapy (CDP) in chronic cancer-associated upper or lower limb lymphedema, although the evidence for MLD alone on the development of lower limb lymphedema is limited.

CQ7: Obesity and weight control

Recommendation

Obesity Upper limbs: probable; lower limbs: limited-no conclusion

Weight control Upper limbs: probable; lower limbs: limited-no conclusion

Obesity

Obesity is considered to be related to lymphedema. Although there have been few high-quality studies, the number of nonrandomized controlled studies and cohort studies regarding the upper limb is increasing, and some corresponding results have been reported.^40–42 Obesity has been found to be a risk factor for the development of lymphedema of the upper limb following breast cancer or its treatment; however, only one study,⁴³ with limited evidence, has shown that obesity can increase the risk of lower limb lymphedema.

Weight control

Two randomized studies have reported a significant reduction in lymphedema of the upper limbs.^44,45

CQ8: Exercise

Recommendation

Prevention Upper limbs: probable; lower limbs: limited-suggestive

Treatment Upper limbs: Grade B; lower limbs: Grade C1

Prevention

Some randomized trials have concluded that exercise in patients at risk of lymphedema after breast cancer surgery reduces its incidence.^46,47

Although we did not find any randomized trials that verified the effectiveness of exercise for lower limb lymphedema, a case–control study on the influence of physical activity for lower limb lymphedema with a focus on walking showed results similar to those observed for upper limb lymphedema.⁴⁸

Treatment

Recent studies are increasingly focusing on this issue. Several types of exercise, such as Pilates, treadmill walking, Nordic walking, and weightlifting, have significantly reduced upper limb volume in patients with secondary lymphedema.^49–55 Small RCTs have shown that daily, home-based exercise programs and self-care or active resistance exercise with CDP did not cause additional swelling. However, they significantly reduced limb volume, contributing to an improved quality of life (QOL).⁵³

Fukushima et al. evaluated the immediate effects of active exercise with compression therapy (AECT) on gynecological cancer-related lower limb lymphedema⁵² in a trial of 23 women with lower limb lymphedema who had completed high-load AECT, low-load AECT, or compression-only therapy. The AECT was performed on a bicycle ergometer with short-stretch bandages. The volume decrement differed significantly among the three interventions (p < 0.05). Lower limb volume was significantly reduced after high-load AECT compared with that recorded after compression-only therapy.

In addition to these studies, only one case-cumulative study evaluated the effect of exercise on lower limb lymphedema.⁵⁵

CQ9: Radiation therapy

Recommendation

Upper limbs

Regional lymph node irradiation: Limited-suggestive. Convincing

Irradiation without regional lymph nodes (breast or chest wall only): Limited-suggestive

Lower limbs

Whole pelvic radiation after pelvic lymph node dissection: Convincing

Whole pelvic radiation as the main therapy: Probable

Upper limbs

Herd-Smith et al. reported that lymphedema was observed in 15.9% of the 1278 patients with breast cancer from an Italian cancer registry. Moreover, postoperative radiation was an independent risk factor for the development of lymphedema.⁵⁴ In the meta-analysis, Tsai et al. reported that the incidence of lymphedema was 1.92-fold greater with irradiation than without it (p < 0.001).⁵⁵ Radiation increases the risk of developing lymphedema from 1.92 to 2.97.^56,57

Lower limbs

Kuroda et al. had conducted a chart review of the onset of lymphedema in 264 patients who received pelvic lymph node dissection with or without para-aortic lymph node dissection.⁵⁸ Of those patients, 17 received radiation, 9 (52.9%) of who developed lymphedema; of the 247 patients who did not receive radiation, 88 (35.6%) developed lymphedema. A Cox hazard analysis was performed, showing a HR of 2.323 (p = 0.023) for pelvic lymph node dissection plus para-aortic lymph node dissection without radiation, and a HR of 2.469 (p = 0.0219) with postoperative radiation. Todo et al. retrospectively examined the development of lymphedema in patients with systematic lymph node dissection for endometrial cancer. Lymphedema developed in 19 of 28 patients (67.9%) who received postoperative radiation and in 89 of 258 patients (34.5%) who did not receive radiation (p = 0.0005).⁵⁹ Nakamura et al. conducted retrospective investigations of 97 patients, who were divided into groups according to radical hysterectomy only, radiation only, or radical hysterectomy plus radiation, and assessed the development of lymphedema. The incidence of lymphedema was 3.4%, 9.5%, and 51.1%, respectively, and was significantly higher in the surgery plus radiation group (p = 0.001).⁶⁰

CQ10: Taxanes

Recommendation

Development of edema: Convincing

Development of lymphedema: Limited-suggestive

Roche et al. compared two groups according to postoperative treatment in 1996 patients with node-positive breast cancer: fluorouracil/epirubicin/cyclophosphamide (FEC) (n = 995) or FEC plus docetaxel (n = 1001).⁶¹ Moderate-to-severe edema was found in 0.3% and 4.8% of the FEC group and the FEC plus docetaxel group, respectively (p < 0.001).⁶¹

Jones et al. compared two adjuvant chemotherapy groups consisting of 1016 patients with breast cancer who had received radical surgery at stages I–III.⁶² Edema appeared to be significantly higher in the TC (paclitaxel–cyclophosphamide) group than in the AC (doxorubicin–cyclophosphamide) group. Lee et al. examined the degree of edema in 63 patients after surgery for early-stage breast cancer, who had received anthracycline-based chemotherapy followed by taxane-based chemotherapy.⁶³ Increased extracellular fluid volume in locations other than the affected limbs had returned to pretreatment levels 6 months after the end of taxane administration. Edema may evolve to lymphedema or be combined with lymphedema. Numerous other retrospective studies have reported that the administration of taxanes was associated with lymphedema.^64,65

CQ11: Multilayer lymphedema bandaging

Recommendation

Upper limbs: Grade B

Lower limbs: Grade C

A meta-analysis of studies on the effect of MLLB on arm lymphedema after breast cancer surgery has revealed that the standardized mean difference was −0.33 in eight pre- and post-intervention studies.⁶⁶ Other cohort and pre- and post-intervention studies have also revealed the effect of MLLB on arm lymphedema in the initial phase of treatment^67–69 Of note, an ankle brachial pressure index <0.5 is a contraindication for compression therapy, and inappropriate compression bandaging can potentially lead to nerve injury in the extremities.

CQ12: Intermittent pneumatic compression for prevention and treatment

Recommendation

Prevention Upper limbs: none; lower limbs: none

Treatment Upper and lower limbs: Recommendation Grade C2

Haghighat et al.⁷⁰ demonstrated that the use of CDT alone or in combination with intermittent pneumatic compression (IPC) significantly reduced limb volume in patients with post-mastectomy lymphedema. Szolnoky et al.⁷¹ has also shown that IPC with MLD provides a synergistic enhancement of the effect of CDT on arm volume reduction. Uzkeser et al.⁷² concluded that the pneumatic compression pump alone did not contribute to reduction of lymphedema. Shao et al.⁷³ reviewed seven RCTs, involving a total of 287 patients. The results showed that the use of IPC could alleviate lymphedema; however, there was no significant difference found between the routine management of lymphedema with or without pneumatic pump.

CQ13: Surgery

Recommendation

Lymphatic–venous anastomosis (LVA): Recommendation Grade C2

Vascularized lymph node transfer (VLNT): Recommendation Grade C2

Liposuction: Recommendation Grade C2

LVA can be considered in the short term for patients with minimal response to CDT or recurrent cellulitis.^74,75 Regarding postoperative complications, infection, lymphorrhea, and flap congestion were observed, and additional surgery was necessary in 22.6% of the patients. Several retrospective studies have reported that the frequency of cellulitis significantly decreased following LVA.^76,77 Prophylactic LVA has been reported to be effective in RCTs and meta-analyses. Technical standardization with long-term follow-up periods is expected^78–80

VLNT improves the obstructed lymphatic function; however, the procedure is invasive, and the highest complication rate was reported to be 30.1%. Therefore, in their systematic review, Carl et al. concluded that VLNT should be applied only to patients with ISL stage late II/III. According to a review by Scaglioni et al., the most frequent donor sites were the inguinal lymph nodes, and the use of the lateral thoracic lymph nodes was associated with less reduction and the highest complication rate.⁷⁹ They concluded that VLNT is an effective option in all stages of lymphedema. Lymphatic flow was improved in 55 of 92 patients, and the incidence of cellulitis was decreased. In a systematic review by Ozturk et al. utilizing a questionnaire, 98 of 105 patients felt their QOL had improved following VLNT.⁸⁰

Hoffner et al. verified the effect of liposuction in terms of QOL, using the Short Form Health Survey-36 by postoperative 1 year for 60 post-mastectomy patients with arm lymphedema.⁸¹ Compared with healthy individuals, only scores on physical factors were improved from baseline; however, they concluded that both physical and mental QOL were generally improved by liposuction.

CQ14: Medicine

Recommendation

Herbal medicine: Recommendation Grade C1

Other than herbal medicine

(1)

Coumarins and benzopyrones: Recommendation Grade D

(2)

Urinate: Recommendation Grade D

(3)

Selenium: Recommendation Grade C2

Herbal medicine is ineffective in preventing secondary lymphedema. Given that all available reports were case reports or case series,^82–84 and since adverse events (e.g., pseudoaldosteronism, interstitial pneumonia, and liver dysfunction) have also been reported, the use of herbal medicine should be considered only when the effects of combined therapy are insufficient.

Clinical trials have investigated the administration of coumarins and benzopyrones for the medical treatment of lymphedema.^85,86

Kasseroller et al. conducted a randomized trial of selenium in 179 patients with secondary upper limb lymphedema after breast cancer surgery.⁸⁶ In their study, they found that the incidence of lymphedema was significantly reduced (p < 0.01). The results of larger clinical trials currently being planned are expected.^87,88

CQ15: Primary lymphedema

Recommendation Grade C1

Lymphedema arising from an abnormal development of the lymphatic system is classified as primary lymphedema.⁸⁹ The largest study conducted thus far, a case series by Schook et al. included 138 patients with onset before the age of 21 years.⁹⁰ Most (75.4%) patients had been treated by compression garments alone or in combination with a pneumatic compression device (19.6%). Thirteen percent of the children had at least one surgery. Lymphedema progression was observed in 57.9% of the patients; however, the disease was basically well managed by compression, without surgery.

In a consensus review, Lee et al. concluded that compliance to CDT, especially compression, is of outmost importance.⁹¹ They mentioned that the surgical option should be considered only when the effectiveness of CDT is limited. Deng et al. performed a cross-sectional study on the secondary data provided by the national lymphedema network of 803 patients to determine the correlation of extremity laterality with lymphedema.⁹²

Conclusion

Footnotes

Acknowledgments

We would like to acknowledge Enago for reviewing our article for language. We also wish to thank the General Corporation Japanese Lymphedema Society for a grant.

Authors' Contributions

Conceptualization: K.K. and S.I. Methodology: S.I. Formal analysis and investigation: K.K., S.I., Y.K., Y.O., K.U., D.Y., and H.O. Writing-original draft preparation: K.K., S.I., Y.K., Y.O., K.U., D.Y., and H.O. Writing-review and editing: K.K. and S.I. All authors read and approved the final version of the article.

Author Disclosure Statement

The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the article.

Funding Information

The authors did not receive support from any organization for the submitted work.

References

Gordon

, Varney

, Keeley

, et al. Update and audit of the St George's classification algorithm of primary lymphatic anomalies: A clinical and molecular approach to diagnosis. J Med Genet, 2020; 57:653–659.

World Cancer Research Fund/ American Institute for Cancer

Research

, Food

Nutrition

. Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington, DC: AICR; 2007.

The AGREE Next Steps Consortium (2009) AGREE II (Appraisal of Guidelines for Research & Evaluation II) May 2009. Available from: https://www.agreetrust.org/agree-ii/. 2013. Accessed on April 1, 2020.

Kojimahara

, Nakayama

, Morizane

, Yamaguchi

, Yoshida

Available from: http://minds4.jcqhc.or.jp/minds/guideline/pdf/manual_all_2017.pdf. Accessed on April 1, 2020.

Executive Committee of the International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema (2020) Consensus document of the International Society of Lymphology. Lymphology, 2020; 53:3–19.

Ministry of Health, Labor and Welfare. Amendment of Distortion in Calculation Method of Medical Fees, Notification No. 52. Tokyo, Japan; 2016.

Ministry of Health, Labor and Welfare. Central Social Insurance Medical Council General Meeting Minutes. Tokyo, Japan; 2016. p. 192–194

Harris

, Hugi

, Olivotto

, Levine

. Steering Committee for Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. Clinical practice guidelines for the care and treatment of breast cancer: Lymphedema. CMJA, 2001; 164:191–199.

, Chen

, Haber

, Guth

, Axelrod

. The effect of providing information about lymphedema on the cognitive and symptom outcomes of breast cancer survivors. Ann Surg Oncol, 2010; 17:1847–1853.

10.

Veronesi

, Paganelli

, Viale

, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med, 2003; 349:546–553.

11.

Galimberti

, Cole

, Zurrida

, et al. Trial 23–01 investigators. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23–01): A phase 3 randomised controlled trial. Lancet Oncol, 2013; 14:297–305.

12.

Donker

, van Tienhoven

, Straver

, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981–22023 AMAROS): A randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol, 2014; 15:1303–1310.

13.

Asdourian

, Skolny

, Brunelle

, Seward

, Salama

, Taghian

. Precautions for breast cancer-related lymphoedema: Risk from air travel, ipsilateral arm blood pressure measurements, skin punctures, extreme temperatures, and cellulitis. Lancet Oncol, 2016; 17:e392–e405.

14.

Showalter

, Brown

, Cheville

, Fisher

, Sataloff

, Schmitz

. Lifestyle risk factors associated with arm swelling among women with breast cancer. Ann Surg Oncol, 2013; 20:842–849.

15.

Ferguson

, Swaroop

, Horick

, et al. Impact of ipsilateral blood draws, injections, blood pressure measurements, and air travel on the risk of lymphedema for patients treated for breast cancer. J Clin Oncol, 2016; 34:691–698.

16.

Bevilacqua

JLB

, Kattan

, Changhong

, et al. Nomograms for predicting the risk of arm lymphedema after axillary dissection in breast cancer. Ann Surg Oncol, 2012; 19:2580–2589.

17.

Hayes

, Cornish

, Newman

. Comparison of methods to diagnose lymphoedema among breast cancer survivors: 6-month follow-up. Breast Cancer Res Treat, 2005; 89:221–226.

18.

Miller

, Colwell

, Horick

, et al. Immediate implant reconstruction is associated with a reduced risk of lymphedema compared to mastectomy alone: A prospective cohort study. Ann Surg, 2016; 263:399–405.

19.

Blanchard

, Arrault

, Vignes

. Positive impact of delayed breast reconstruction on breast-cancer treatment-related arm lymphoedema. J Plast Reconstr Aesthet Surg, 2012; 65:1060–1063.

20.

Crosby

, Card

, Liu

, Lindstrom

, Chang

. Immediate breast reconstruction and lymphedema incidence. Plast Reconstr Surg, 2012; 129:789e–795e.

21.

Menezes

, Bello

, Millen

, et al. Breast reconstruction and risk of lymphedema after mastectomy: A prospective cohort study with 10 years of follow-up. J Plast Reconstr Aesthet Surg, 2016; 69:1218–1226.

22.

Soran

, Ozmen

, McGuire

, et al. The importance of detection of subclinical lymphedema for the prevention of breast cancer-related clinical lymphedema after axillary lymph node dissection; a prospective observational study. Lymph Res Biol, 2014; 12:289–294.

23.

Hansdorfer-Korzon

, Teodorczyk

, Gruszecka

, Wydra

, Lass

. Relevance of low-pressure compression corsets in physiotherapeutic treatment of patients after mastectomy and lymphadenectomy. Patient Prefer Adherence, 2016; 10:1177–1187.

24.

Sawan

, Mugnai

, Lopes Ade

, Hughes

, Edmondson

. Lower-limb lymphedema and vulval cancer: Feasibility of prophylactic compression garments and validation of leg volume measurement. Int J Gynecol Cancer, 2009; 19:1649–1654.

25.

Stuiver

, de Rooij

, Lucas

, et al. No evidence of benefit from class-II compression stockings in the prevention of lower-limb lymphedema after inguinal lymph node dissection: Results of a randomized controlled trial. Lymphology, 2013; 46:120–131.

26.

Rogan

, Taeymans

, Luginbuehl

, Aebi

, Mahnig

, Gebruers

. Therapy modalities to reduce lymphoedema in female breast cancer patients: A systemic review and meta-analysis. Breast Cancer Res Treat, 2016; 159:1–14.

27.

Vignes

, Porcher

, Arrault

, Dupuy

. Long-term management of breast cancer-related lymphedema after intensive decongestive physiotherapy. Breast Cancer Res Treat, 2007; 101:285–290.

28.

Finnane

, Janda

, Hayes

. Review of the evidence of lymphedema treatment effect. Am J Phys Med Rehabil, 2015; 94:483–498.

29.

Lasinski

, McKillip Thrift

, Squire

, et al. A systematic review of the evidence for complete decongestive therapy in the treatment of lymphedema from 2004 to 2011. PM R, 2012; 4:580–601.

30.

Devoogdt

, Christiaens

, Geraerts

, et al. Effect of manual lymph drainage in addition to guidelines and exercise therapy on arm lymphoedema related to breast cancer: Randomised controlled trial. BMJ, 2011; 343:d5326.

31.

Zimmermann

, Wozniewski

, Szklarska

, Lipowicz

, Szuba

. Efficacy of manual lymphatic drainage in preventing secondary lymphedema after breast cancer surgery. Lymphology, 2012; 45:103–112.

32.

Lacomba

, Yuste Sánchez

, Zapico Goñi

, et al. Effectiveness of early physiotherapy to prevent lymphoedema after surgery for breast cancer: Randomised, single blinded, clinical trial. BMJ, 2010; 340:b5396.

33.

Dönmez

, Kapucu

. The effectiveness of a clinical and home-based physical activity program and simple lymphatic drainage in the prevention of breast cancer-related lymphedema: A prospective randomized controlled study. Eur J Oncol Nurs, 2017; 31:12–21.

34.

Williams

, Vadgama

, Franks

, Mortimer

. A randomized controlled crossover study of manual lymphatic drainage therapy in women with breast cancer-related lymphoedema. Eur J Cancer Care, 2002; 11:254–261.

35.

Andersen

, Højris

, Erlandsen

, Andersen

. Treatment of breast-cancer-related lymphedema with or without manual lymphatic drainage—A randomized study. Acta Oncol, 2000; 39:399–405.

36.

Gradalski

, Ochalek

, Kurpiewska

. Complex decongestive lymphatic therapy with or without vodder ii manual lymph drainage in more severe chronic postmastectomy Upper limb lymphedema: A randomized noninferiority prospective study. J Pain Symptom Manag, 2015; 50:750–757.

37.

Shao

, Zhong

. Manual lymphatic drainage for breast cancer-related lymphoedema. Eur J Cancer Care, 2017; 26. DOI: 10.1111/ecc.12517.

38.

Szuba

, Cooke

, Yousuf

, Rockson

. Decongestive lymphatic therapy for patients with cancer-related or primary lymphedema. Am J Med, 2000; 109:296–300.

39.

Liao

, Huang

, Li

, et al. Complex decongestive physiotherapy for patients with chronic cancer-associated lymphedema. J Formos Med Assoc, 2004; 103:344–348.

40.

Can

, Ekşioğlu

, Bahtiyarca

, Çakcı FA. Assessment of risk factors in patients who presented to the outpatient clinic for breast cancer-related lymphedema. J Breast Health, 2016; 12:31–36.

41.

, Axelrod

, Guth

, et al. Patterns of obesity and lymph fluid level during the first year of breast cancer treatment: A prospective study. J Pers Med, 2015; 5:326–340.

42.

Swenson

, Nissen

, Leach

, Post-White

. Case-control study to evaluate predictors of lymphedema after breast cancer surgery. Oncol Nurs Forum, 2009; 36:185–193.

43.

Yost

, Cheville

, Al-Hilli

, et al. Lymphedema after surgery for endometrial cancer: Prevalence, risk factors, and quality of life. Obstet Gynecol, 2014; 124:307–315.

44.

Shaw

, Mortimer

, Judd

. A randomized controlled trial of weight reduction as a treatment for breast cancer-related lymphedema. Cancer, 2007; 110:1868–1874.

45.

Schmitz

, Ahmed

, Troxel

, et al. Weight lifting for women at risk for breast cancer-related lymphedema: A randomized trial. JAMA, 2010; 304:2699–2705.

46.

Brown

, John

, Segal

, Chu

, Schmitz

. Physical activity and lower limb lymphedema among uterine cancer survivors. Med Sci Sports Exerc, 2013; 45:2091–2097.

47.

Şener

HÖ

, Malkoç M, Ergin G, Karadibak D, Yavuzşen T. Effects of clinical Pilates exercises on patients developing lymphedema after breast cancer treatment: A randomized clinical trial. J Breast Health, 2017; 13:16–22.

48.

Di Blasio

, Morano

, Bucci

, et al. Physical exercises for breast cancer survivors: Effects of 10 weeks of training on upper limb circumferences. J Phys Ther Sci, 2018; 28:2778–2784.

49.

Smoot

, Zerzan

, Krasnoff

, Wong

, Cho

, Dodd

. Upper extremity bioimpedance before and after treadmill testing in women post breast cancer treatment. Breast Cancer Res Treat, 2014; 148:445–453.

50.

Schmitz

, Ahmed

, Troxel

, et al. Weight lifting in women with breast-cancer-related lymphedema. N Engl J Med, 2009; 361:664–673.

51.

Jeffs

, Wiseman

. Randomised controlled trial to determine the benefit of daily home-based exercise in addition to self-care in the management of breast cancer-related lymphoedema: A feasibility study. Support Care Cancer, 2013; 21:1013–1023.

52.

Fukushima

, Tsuji

, Sano

, et al. Immediate effects of active exercise with compression therapy on lower-limb lymphedema. Support Care Cancer, 2017; 25:2603–2610.

53.

Katz

, Dugan

, Cohn

, Chu

, Smith

, Schmitz

. Weight lifting in patients with lower-extremity lymphedema secondary to cancer: A pilot and feasibility study. Arch Phys Med Rehabil, 2010; 91:1070–1076.

54.

Herd-Smith

, Russo

, Muraca

, Del Turco

, Cardona

. Prognostic factors for lymphedema after primary treatment of breast carcinoma. Cancer, 2001; 92:1783–1787.

55.

Tsai

, Dennis

, Lynch

, Snetselaar

, Zamba

, Scott-Conner

. The risk of developing arm lymphedema among breast cancer survivors: A meta-analysis of treatment factors. Ann Surg Oncol, 2009; 16:1959–1972.

56.

Nguyen

, Hoskin

, Habermann

, Cheville

, Boughey

. Breast cancer-related lymphedema risk is related to multidisciplinary treatment and not surgery alone: Results from a large cohort study. Ann Surg Oncol, 2017; 24:2972–2980.

57.

Kilbreath

, Refshauge

, Beith

, et al. Risk factors for lymphoedema in women with breast cancer: A large prospective cohort. Breast, 2016; 28:29–36.

58.

Kuroda

, Yamamoto

, Yanagisawa

, et al. Risk factors and a prediction model for lower limb lymphedema following lymphadenectomy in gynecologic cancer: A hospital-based retrospective cohort study. BMC Women Health, 2017; 17:50.

59.

Todo

, Yamamoto

, Minobe

, et al. Risk factors for postoperative lower-extremity lymphedema in endometrial cancer survivors who had treatment including lymphadenectomy. Gynecol Oncol, 2010; 119:60–64.

60.

Nakamura

, Masuyama

, Ida

, et al. Radical hysterectomy plus concurrent chemoradiation/radiation therapy is negatively associated with return to work in patients with cervical cancer. Int J Gynecol Cancer, 2017; 27:117–122.

61.

Roché

, Fumoleau

, Spielmann

, et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: The FNCLCC PACS 01 Trial. J Clin Oncol, 2006; 24:5664–5671.

62.

Jones

, Savin

, Holmes

, et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol, 2006; 24:5381–5387.

63.

Lee

, Beith

, Ward

, Kilbreath

. Lymphedema following taxane-based chemotherapy in women with early breast cancer. Lymphat Res Biol, 2014; 12:282–288.

64.

Ohsumi

, Shimozuma

, Ohashi

, et al. Subjective and objective assessment of edema during adjuvant chemotherapy for breast cancer using taxane-containing regimens in a randomized controlled trial: The National Surgical Adjuvant Study of Breast Cancer 02. Oncology, 2012; 82:131–138.

65.

Beuselinck

, Wildiers

, Wynendaele

, Dirix

, Kains

, Paridaens

. Weekly paclitaxel versus weekly docetaxel in elderly or frail patients with metastatic breast carcinoma: A randomized phase-II study of Belgian Society of Medical Onclogy. Crit Rev Oncol Hematol, 2010; 75:70–77.

66.

McNeely

, Magee

, Lees

, Bagnall

, Haykowsky

, Hanson

. The addition of manual lymph drainage to compression therapy for breast cancer related lymphedema: A randomized controlled trial. Breast Cancer Res Treat, 2004; 86:95–106.

67.

Smykla

, Walewicz

, Trybulski

, et al. Effect of kinesiology taping on breast cancer-related lymphedema: A randomized single-blind controlled pilot study. Bio Med Res Int, 2013; 2013:767106.

68.

Flour

, Clark

, Partsch

, et al. Dogmas and controversies in compression therapy: Report of an international compression club (ICC) meeting, Brussels, May 2011. Int Wound J, 2013; 10:516–526.

69.

Kara

, Ozçakar

, Malas

, Kara

, Altundağ K. Median, ulnar, and radial nerve entrapments in a patient with breast cancer after treatment for lymphedema. Am Surg, 2011; 77:248–249.

70.

Haghighat

, Lotfi-Tokaldany

, Yunesian

, Akbari

, Nazemi

, Weiss

. Comparing two treatment methods for post mastectomy lymphedema: Complex decongestive therapy alone and in combination with intermittent pneumatic compression. Lymphology, 2010; 43:25–33.

71.

Szolnoky

, Lakatos

, Keskeny

, et al. Intermittent pneumatic compression acts synergistically with manual lymphatic drainage in complex decongestive physiotherapy for breast cancer treatment-related lymphedema. Lymphology, 2009; 42:188–194.

72.

Uzkeser

, Karatay

, Erdemci

, Koc

, Senel

. Efficacy of manual lymphatic drainage and intermittent pneumatic compression pump use in the treatment of lymphedema after mastectomy: A randomized controlled trial. Breast Cancer, 2015; 22:300–307.

73.

Shao

, Qi

, Zhou

, Zhong

. Intermittent pneumatic compression pump for breast cancer-related lymphedema: A systematic review and meta-analysis of randomized controlled trials. Oncol Res Treat, 2014; 37:170–174.

74.

Carl

, Walia

, Bello

, et al. Systematic review of the surgical treatment of extremity lymphedema. J Reconstr Microsurg, 2017; 33:412–425.

75.

Basta

, Gao

, Wu

. Operative treatment of peripheral lymphedema: A systematic meta-analysis of the efficacy and safety of lymphovenous microsurgery and tissue transplantation. Plast Reconstr Surg, 2014; 133:905–913.

76.

Gennaro

, Gabriele

, Salini

, et al. Our supramicrosurgical experience of lymphaticovenular anastomosis in lymphoedema patients to prevent cellulitis. Eur Rev Med Pharmacol Sci, 2017; 21:674–679.

77.

Winters

, Tielemans

HJP

, Hameeteman

, et al. The efficacy of lymphaticovenular anastomosis in breast cancer-related lymphedema. Breast Cancer Res Treat, 2017; 165:321–327.

78.

Jørgensen

, Toyserkani

, Sørensen

. The effect of prophylactic lymphovenous anastomosis and shunts for preventing cancer-related lymphedema: A systematic review and meta-analysis. Microsurgery, 2018; 38:576–585.

79.

Scaglioni

, Arvanitakis

, Chen

, et al. Comprehensive review of vascularized lymph node transfers for lymphedema: Outcomes and complications. Microsurgery, 2018; 38:222–229.

80.

Ozturk

, Ozturk

, Glasgow

, et al. Free vascularized lymph node transfer for treatment of lymphedema: A systematic evidence based review. J Plast Reconstr Aesthet Surg, 2016; 69:1234–1247.

81.

Hoffner

, Bagheri

, Hansson

, Manjer

, Troëng

, Brorson

. SF-36 shows increased quality of life following complete reduction of postmastectomy lymphedema with liposuction. Lymphat Res Biol, 2017; 15:87–98.

82.

Nagai

, Shibamoto

, Ogawa

. Therapeutic effects of saireito (chai-ling-tang), a traditional Japanese herbal medicine, on lymphedema caused by radiotherapy: A case series study. Evid Based Complement Alternat Med, 2013; 2013:241629.

83.

Komiyama

, Takeya

, Takahashi

, Yamamoto

, Kubushiro

. Feasibility study on the effectiveness of Goreisan-based Kampo therapy for lower abdominal lymphedema after retroperitoneal lymphadenectomy via extraperitoneal approach. J Obstet Gynecol Res, 2015; 41:1449–1456.

84.

Casley-Smith

, Morgan

, Piller

. Treatment of lymphedema of the arms and legs with 5,6- benzo-[alpha]-pyrone. N Engl J Med, 1993; 329:1158–1163.

85.

Badger

CMA

, Preston

, Seers

, Mortimer

. Benzo-pyrones for reducing and controlling lymphoedema of the limbs. Cochrane Database Syst Rev, 2004:CD003140. DOI: 10.1002/14651858.

86.

Kasseroller

, Schrauzer

. Treatment of secondary lymphedema of the arm with physical decongestive therapy and sodium selenite: A review. Am J Ther, 2000; 7:273–279.

87.

Zimmermann

, Leonhardt

, Kersting

, Albrecht

, Range

, Eckelt

. Reduction of postoperative lymphedema after oral tumor surgery with sodium selenite. Biol Trace Elem Res, 2005; 106:193–203.

88.

Pfister

, Dawzcynski

, Schingale

. Sodium selenite and cancer related lymphedema: Biological and pharmacological effects. J Trace Elem Med Biol, 2016; 37:111–116.

89.

Lee

, Villavicencio

. Primary lymphoedema and lymphatic malformation: Are they the two sides of the same coin?. Eur J Vasc Endovasc Surg, 2010; 39:646–653.

90.

Schook

, Mulliken

, Fishman

, Grant

, Zurakowski

, Greene

. Primary lymphedema: Clinical features and management in 138 pediatric patients. Plast Reconstr Surg, 2011; 127:2419–2431.

91.

Lee

, Andrade

, Antignani

, et al. Diagnosis and treatment of primary lymphedema. Consensus document of the International Union of Phlebology (IUP)-2013. Int Angiol, 2013; 32:541–574.

92.

Deng

, Radina

, Fu

, et al. Self-care status, symptom burden, and reported infections in individuals with lower-extremity primary lymphedema. J Nurs Scholarsh, 2015; 47:126–134.