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Morbidity after lymph node dissection in patients with cancer: Incidence, risk factors, andprevention

Stuiver, M.M.

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Incidence, risk factors, and prevention

MORBIDITY AFTER LYMPH NODE DISSECTION IN PATIENTS WITH CANCER

Martijn M. Stuiver

MO

RBIDITY AFTER LYM

PH N

OD

E DISSEC

TION

IN PATIEN

TS WITH

CAN

CER

Martijn M

. Stuiver

UITNODIGINGVoor het bijwonen van de openbare

verdediging van het proefschrift:

Door Martijn M. Stuiver

Dinsdag 17 juni 2014 om 16:00 uur

Agnietenkapel, Universiteit van Amsterdam

Oudezijds Voorburgwal 229 - 2311012 EZ Amsterdam

Receptie na afl oop van de promotie

Paranimfen:

Marieke ten [email protected]

Sander de [email protected]

Martijn StuiverKastanjelaan 19

1431 JB [email protected]

06-50614484




1



2

ColofonCopyright © 2014: M. M. Stuiver

Vormgeving:

www.youre-on.tv

Uitgegeven door: Het Nederlands Kanker Instituut - Antoni van Leeuwenhoek

ISBN: 978-90-5335-873-3

dit proefschift is

gedrukt op FSC®

gecertificeerd papier.

3

ACADEMISCH PROEFSCHRIFTter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam

op gezag van de Rector Magnificus

prof. dr. D.C. van den Boom

ten overstaan van een door het college

voor promoties ingestelde commissie,

in het openbaar te verdedigen in de Agnietenkapel

op dinsdag 17 juni 2014, te 16.00 uur

door

Martijn Matthias Stuivergeboren te Aalsmeer


MORBIDITY AFTER

LYMPH NODE DISSECTION IN PATIENTS

WITH CANCER

4

Promotiecommissie:

Promotores: Prof. Dr. N.K. Aaronson

Prof. Dr. P.M.M. Bossuyt

Co-promotores: Dr. C. Lucas

Dr. O.E. Nieweg

Overige leden: Prof. Dr. R.H.H. Engelbert

Prof. Dr. R.J.P.M. Scholten

Prof. Dr. M.A.G. Sprangers

Prof. Dr. E.J.Th. Rutgers

Prof. Dr. M.W.M. van den Brekel

Prof. Dr. S. Horenblas

Faculteit der Maatschappij- en Gedragswetenschappen

5

TABLE OF CONTENTSChapter 1 7General Introduction and outline

Chapter 2 15Surgical wound complications after groin dissection in melanoma patients,

a historical cohort study and risk factor analysis

Chapter 3 29Early wound complications after inguinal lymphadenectomy in penile cancer,

a historical cohort study and risk factor analysis.

Chapter 4 43No evidence of benefit from class-II compression stockings in the prevention

of lower-limb lymphoedema after inguinal lymph node dissection;

Results of a randomized controlled trial

Chapter 5 59Conservative interventions for preventing clinically detectable upper-limb lymphoedema

in patients who are at risk of developing lymphoedema after breast cancer therapy

Chapter 6 121Impact of shoulder complaints after neck dissection on shoulder disability

and quality of life

Chapter 7 137Psychometric properties of three patient reported outcome measures

for the assessment of shoulder disability after neck dissection

Chapter 8 157General discussion and future directives

Summary 164CV, portfolio, dankwoord

6

7

CHAPTER 1General Introduction and Outline

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The role of lymph node dissection in cancer treatmentFor solid tumors, surgical intervention is still the primary curative treatment modality for many types

of cancer. In patients with regional lymph node involvement, whether clinically apparent at diagnosis

or established by sentinal node biopsy or by ultrasound guided fine needle biopsy, a lymph node

dissection is carried out to achieve locoregional control and prevent further dissemination of the

disease. In some cases, lymph node dissection is part of the standard procedure for surgical treatment

with curative intent, even if there is no clinical evidence of pathological nodes. Regional lymph node

dissection can also be performed as a salvage procedure after primary chemoradiation therapy in

head and neck cancer. While it is an important part of surgical treatment for locally advanced cancer,

lymph node dissection is also associated with both short-term and long-term morbidity.

Wound complications following inguinal lymph node dissectionAs with any surgical procedure, wound complications may occur following lymph node dissection.

Wound complications, such as wound infection, seroma formation, skin edge necrosis and wound

breakdown, account for an important part of short-term morbidity after lymph node dissection.

While wound complications can occur after lymph node dissection in any anatomical region, the

inguinal lymph node dissection (ILND) as carried out in patients with established inguinal lymph node

metastases of melanoma, penile- or vulvar cancer, appears to be particularly complication prone 1-4.

Previous studies have addressed the risk factors associated with wound complications in ILND, but

both the design and the results of these studies have not been entirely consistent (e.g., not all studies

investigated the same set of risk factors; not all studies that examined any given risk factor yielded

significant results) 1,4-8. Risk factors may be related to postoperative management, such as bed rest or

suction drain management. Also, clinical and patient characteristics may play a role, i.e. technique and

extent of the ILND, comorbidity, age or smoking behaviour.

Identifying risk factors for surgical complications may offer opportunities to reduce postoperative

morbidity and improve patient outcomes for high-risk patients. The inconsistent findings of previous

studies suggest the need for further research in this area. The Netherlands Cancer Institute is a

specialised cancer hospital, and consequently has a high case load of patients who have undergone

an inguinal lymph node dissection. Taking advantage of this high case load, two historical cohort

studies were carried out to assess the incidence and risk factors of postoperative complications in

patients with groin dissection for melanoma and penile carcinoma respectively. These studies are

reported in Chapter 2 and 3.

Lymphoedema after lymph node dissectionWith more patients surviving cancer, increasing attention is being given to long term sequelae of

cancer treatment and their impact on health-related quality of life (HRQoL). The most frequently

reported long term complication after lymph node dissection, and one of the most bothersome, is

lymphoedema. Lymphoedema is the accumulation of interstitial fluid as a result of insufficient lymph

drainage 9.

After lymph node dissection, secondary lymphoedema may occur as a result of insufficient lymph

drainage due to removal of the lymphnodes. Disruption of collateral pathways due to scar tissue

formation and fibroses, resulting from the surgical procedure and/ or subsequent radiotherapy

9

may add to the risk of developing lymphoedema. When untreated, accumulation of proteins in the

lymphatic fluid will lead to increased viscosity of the lymphoedema, further impairing drainage, and

ultimately to fibrosis. Lymphoedema can cause pain and discomfort, and limit activities thus impairing

HRQoL 10-14.

Several criteria have been put forward for the diagnosis of clinically relevant lymphoedema, and

several methods of measurement are available. Most criteria as used in research are based on

quantitative changes in circumference or volume, with differing thresholds for defining the presence

of lymphoedema. More sophisticated methods such as bio-impedance and ultrasound measurements

are sometimes also used 15-17.

As part of usual care, several interventions can be offered to patients after lymph node dissection

to reduce the risk of developing lymphoedema. There is, however, considerable practice variation.

Preventive interventions may include education on risk-reduction strategies, self care and surveillance

for early signs and symptoms of lymphoedema 18,19. The use of compression stockings or sleeves has

been advocated 20-22. Also, manual lymph drainage is believed by some to be an effective intervention

for reduction of lymphoedema risk after lymph node dissection 22-24. Strong empirical evidence on the

effectiveness of these preventive interventions is scarce, with no available systematic reviews and, for

some therapies, no randomized controlled trials.

Chapter 4 reports on a randomized controlled trial for prevention of lower limb lymphoedema after

inguinal lymph node dissection by use of compression stockings.

Chapter 5 reports on a systematic review of randomised controlled trials on conventional interven-

tions for prevention of lymphoedema in patients who are at risk for upper limb lymphoedema after

breast cancer treatment.

The shoulder syndrome after neck dissectionPersisting lymphoedema is less well documented after neck dissection compared to axillary or

inguinal lymph node dissection, although recent studies report incidence rates as high as 79% 25-27.

The most important long term complication after neck dissection is related to iatrogenic damage of

the eleventh cranial nerve; the accessory nerve 28-31.

Dysfunction of the accessory nerve results in paresis or paralysis of the trapezius muscle. In healthy

persons, the trapezius muscle stabilizes the scapula on the thorax, during positioning and movements

of the arm. While glenohumeral range of motion for abduction and forward flexion in the shoulder

joint is limited to 90 degrees, the forward and lateral rotation of the scapula permits the arm to elevate

up to 180 degrees in forward flexion or abduction. In these movements, the trapezius muscle is an

important contributor to combined forward and lateral rotation, and elevation of the scapula. It is the

sole muscle capable of lateral rotation of the scapula. Consequently, range of motion of the shoulder

girdle is severely limited when the trapezius muscle is dysfunctional. Aside from limited (active) range

of motion, dysfunction of the trapezius muscle may lead to changes in posture. The scapula tends

to drop, rotate medially, and the shoulder girdle goes into protraction. This causes overload of the

rhomboid muscles, the levator scapulae muscle, and the acromio-clavicular and sterno-clavicular

joints. Secondary to these changes in anatomical position and changed scapulo-thoracic pattern of

movement, patients experience shoulder joint problems such as pain and even secondary adhesive

capsulitis 31,32.

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In 1952, Ewing labelled the combination of shoulder drop, winging of the scapula due to inadequate

stabilization, limited range of motion and changes in functional anatomy the ‘shoulder syndrome’ in

patients after neck dissection 33. Since then, a number of elective procedures have been developed to

limit postoperative morbidity by preserving non-lymphatic structures such as the accessory nerve and

the sternocleidomastoid muscle. To date, such modified or selective neck dissections are the norm,

and radical neck dissection with sacrifice of the accessory nerve is performed only if there is direct

involvement of the nerve in the pathological process.

Still, even after nerve sparing dissections, the majority of patients experience temporary loss of

function of the trapezius muscle 28,30. Although recovery of the accessory nerve typically occurs when

it has not been dissected during the procedure, recovery usually does not set in before 6 months after

surgery and it can take as long as 12 months for the trapezius muscle to regain its function 34. This

means that even in patients with a good prognosis for functional recovery of the shoulder, disability

may occur in the mid-long term. Aside from shoulder problems, the extensive surgery and subsequent

scar formation may impair cervical range of motion. Chapter 6 reports on a prospective clinical study

to determine incidence and recovery patterns of shoulder- and neck function after neck dissection,

and to identify risk factors of shoulder disability after neck dissection in the mid-term postoperative

period.

The reported incidence and prevalence of shoulder pain and disability after neck dissection varies

widely, and is dependent on the type of dissection 35. Part of the variability in observed shoulder

disability arises from the diversity of outcome measures used. This complicates the interpretation of

results across studies investigating shoulder disability after neck dissection. Moreover, the patient

reported outcome measures that have been used in patients after neck dissection have been insuffi-

ciently validated in this population 35,36.

Chapter 7 reports the results of a study of the psychometric properties of 3 commonly used scales to

measure shoulder disability in patients after neck dissection. Chapter 8 provides an overall summary

and discussion of the research contained in this thesis.

Relevance of the studies in this thesisSummarizing, lymph node dissection is still the de facto standard in surgical treatment of patients

with regional lymph node involvement. It is associated with a variety of complications that may impact

negatively on patients’ functioning, activities and quality of life. This thesis adds to the current body

of knowledge by reporting on the incidence, impact, risk factors and prevention of a number of

important lymph node dissection-related sequelae in patients with breast-, vulvar-, penile-, skin- and

head and neck cancer.

11

REFERENCES1. Poos HPAM, Kruijff S, Bastiaannet E, van Ginkel RJ, Hoekstra HJ. Therapeutic groin dissection

for melanoma: Risk factors for short term morbidity. Eur J Surg Oncol; 2009 Aug 1;35:877–83.

2. Spiess PE, Hernandez MS, Pettaway CA. Contemporary inguinal lymph node dissection: minimizing complications. World J Urol. 2008;27:205–12.

3. Gould N. Predictors of Complications after Inguinal Lymphadenectomy. Gynecol Oncol. 2001;82:329–32.

4. Chang SB, Askew RL, Xing Y, Weaver S, Gershenwald JE, Lee JE, et al. Prospective assessment of postoperative complications and associated costs following inguinal lymph node dissection (ILND) in melanoma patients. Ann Surg Oncol. 2010;17:2764– 72.

5. Wevers KP, Poos H, van Ginkel RJ, van Etten B. Early mobilization after ilio-inguinal lymph node dissection for melanoma does not increase the wound complication rate. Eur J Surg Oncol. 2012;39:185-90.

6. Gaarenstroom KN, Kenter GG, Trimbos JB, Agous I, Amant F, Peters AAW, et al. Postoperative complications after vulvectomy and inguinofemoral lymphadenectomy using separate groin incisions. Int J Gynecol Cancer. 2003;13:522–7.

7. Serpell JW, Carne PWG, Bailey M. Radical lymph node dissection for melanoma. ANZ J Surg. 2003;73:294–9.

8. Abbas S, Seitz M. Systematic review and meta-analysis of the used surgical techniques to reduce leg lymphedema following radical inguinal nodes dissection. Surg Oncol. 2011;20:88–96.

9. Brennan MJ. Lymphedema following the surgical treatment of breast cancer: A review of patho-physiology and treatment. J Pain Symptom Manage 1992;7:110–6.

10. Paskett ED, Naughton MJ, McCoy TP, Case LD, Abbott JM. The epidemiology of arm and hand swelling in premenopausal breast cancer survivors. Cancer Epidemiol Biomarkers Prev. 2007 Apr;16:775–82.

11. Vassard D, Olsen MH, Zinckernagel L, Vibe-Petersen J, Dalton SO, Johansen C. Psychological consequences of lymphoedema associated with breast cancer: A prospective cohort study. Eur J Cancer. 2010;46:3211–8.

12. Ryan M, Stainton CM, Jaconelli C, Watts S, MacKenzie P, Mansberg T. The Experience of Lower Limb Lymphedema for Women After Treatment for Gynecologic Cancer. Oncol Nurs Forum. 2003;30:417–23.

13. Cheville AL, Almoza M, Courmier JN, Basford JR. A prospective cohort study defining utilities using time trade-offs and the Euroqol-5D to assess the impact of cancer- related lymphedema. Cancer. 2010;116:3722–31.

14. Disipio T, Rye S, Newman B, Hayes S. Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis. Lancet Oncol. 2013;14:500–15.

15. Adriaenssens N, Belsack D, Buyl R, Ruggiero L, Breucq C, De Mey J, et al. Ultrasound elastog-raphy as an objective diagnostic measurement tool for lymphoedema of the treated breast in breast cancer patients following breast conserving surgery and radiotherapy. Radiol Oncol. 2012;46:284–95.

16. Box RC, Reul-Hirche HM, Bullock-Saxton JE, Furnival CM. Physiotherapy after breast cancer surgery: results of a randomised controlled study to minimise lymphoedema. Breast Cancer Res Treat. 2002;75:51–64.

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17. Piso DU, Eckardt A, Liebermann A, Gutenbrunner C, Schäfer P, Gehrke A. Early rehabilitation of head-neck edema after curative surgery for orofacial tumors. Am J Phys Med Rehabil. 2001;80:261–9.

18. Meneses KD, McNees MP. Upper extremity lymphedema after treatment for breast cancer: a review of the literature. Ostomy Wound Manage. 2007;53:16–29.

19. Stout Gergich NL, Pfalzer LA, McGarvey C, Springer B, Gerber LH, Soballe P. Preoperative assessment enables the early diagnosis and successful treatment of lymphedema. Cancer. 2008;112:2809–19.

20. Nelson BA, Cookson MS, Smith JA, Chang SS. Complications of inguinal and pelvic lymphad-enectomy for squamous cell carcinoma of the penis: a contemporary series. J Urol. 2004;172:494–7.

21. Karakousis CP. Surgical procedures and lymphedema of the upper and lower extremity. J Surg Oncol. 2006;93:87–91.

22. Castro-Sánchez AM, Moreno-Lorenzo C, Matarán-Peñarrocha GA, Aguilar-Rerrándiz ME, Almagro-Céspedes IA, Anaya-Ojeca J. Prevención del linfedema tras cirurgia de cáncer de mamma mediante ortesis elástica de contenctión y drenaje linfático manual: ensay clínico aleato-rizado. Med Clin Barc. 2011;5:204–7.

23. Lacomba MT, Sánchez M, Goñi ÁZ. Effectiveness of early physiotherapy to prevent lymphoedema after surgery for breast cancer: randomised, single blinded, clinical trial. BMJ. 2010; b5396

24. Zimmermann A, Szkalrska A, Lipowicz A, Wozniewski M. Einfluss Der Manuellen Lymphdrainage Auf Die Schulterbeweglichkeit Nach Brustkrebsoperation . Pt_Zeitschrift für Physiotherapeuten. 2009;7:602–10.

25. Deng J, Ridner SH, Dietrich MS, Wells N, Murphy BA. Assessment of external lymphedema in patients with head and neck cancer: a comparison of four scales. Oncol Nurs Forum. 2013;40:501–6.

26. Deng J, Murphy BA, Dietrich MS, Wells N, Wallston KA, Sinard RJ, et al. Impact of secondary lymphedema after head and neck cancer treatment on symptoms, functional status, and quality of life. Head Neck. 2012;35:1026–35.

27. Cormier JN, Askew RL, Mungovan KS, Xing Y, Ross MI, Armer JM. Lymphedema beyond breast cancer: a systematic review and meta-analysis of cancer-related secondary lymphedema. Cancer. 2010;116:5138–49.

28. Dijkstra PU, van Wilgen CP, Buijs RP, Brendeke W, de Goede CJ, Kerst A, et al. Incidence of shoulder pain after neck dissection: a clinical explorative study for risk factors. Head Neck. 2001;23:947–53.

29. Shah S, Har-El G, Rosenfeld RM. Short-term and long-term quality of life after neck dissection. Head Neck. 2001;23:954–61.

30. van Wilgen CP, Dijkstra PU, van der Laan BFAM, Plukker JTM, Roodenburg JLN. Shoulder complaints after nerve sparing neck dissections. Int J Oral Maxillofac Surg. 2004;33:253–7.

31. Salerno G, Cavaliere M, Foglia A, Pellicoro DP, Mottola G, Nardone M, et al. The 11th nerve syndrome in functional neck dissection. Laryngoscope. 2002;112(7 Pt 1):1299– 307.

32. Patten C, Hillel AD. The 11th Nerve Syndrome: Accessory Nerve Palsy or Adhesive Capsulitis? Arch Otolaryngol Head Neck Surg. 1993;119:215–20.

33. Ewing MR, Martin H. Disability following radical neck dissection; an assessment based on the postoperative evaluation of 100 patients. Cancer. 1952;5:873–83.

34. Laverick S, Lowe D, Brown JS, Vaughan ED, Rogers SN. The Impact of Neck Dissection on Health-Related Quality of Life. Arch Otolaryngol Head Neck Surg. 2004;130:149– 54.

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35. Goldstein DP, Ringash J, Bissada E, Jaquet Y, Irish J, Chepeha D, et al. Scoping review of the liter-ature on shoulder impairments and disability after neck dissection. Head Neck. 2013; 36:299-308

36. Goldstein DP, Ringash J, Bissada E, Jacquet Y, Irish J, Chepeha D, et al. Evaluation of shoulder disability questionnaires used for the assessment of shoulder disability after neck dissection for head and neck cancer. Head Neck. 2013 doi:10.1002/hed.23490 C

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CHAPTER 2Surgical wound complications after groin dissection in melanoma patients – a historical cohort study and risk factor analysis

M.M. Stuiver, MSc1,2

E. Westerduin, MD3

S. ter Meulen, MANP3

A. D. Vincent PhD4

O.E. Nieweg, MD, PhD3

M.W.J.M. Wouters, MD, PhD3

1 The Netherlands Cancer Institute, Department of Physiotherapy2 Academic Medical Centre – University of Amsterdam, Department of Clinical Epidemiology Biostatistics and Bioinformatics3 The Netherlands Cancer Institute, Skin and Melanoma Center and Department of Surgical Oncology4 The Netherlands Cancer Institute, Deptartment of Biostatistics

Accepted January 2013; European Journal of Surgical Oncology

Available online http://dx.doi.org/10.1016/j.ejso.2014.01.019

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ABSTRACTBackground and ObjectivesWound complications occur frequently after inguinal lymph node dissection (ILND) in melanoma

patients. Evidence on risk factors for complications is scarce and inconsistent. This study assessed

wound complication rates after ILND and investigated associated risk factors, in the melanoma unit of

a specialised cancer hospital.

MethodsA chart review was conducted of all patients on whom inguinal lymp node dissection had been

performed between 2003 and 2013. Wound infections, seroma formation and skin flap problems

were assessed according to explicit definitions and graded through the modified Clavien system.

Univariable and multivariable penalized logistic regression was used to identify risk factors. The

primary factors of interest were body mass index, age, smoking, diabetes, cardiovascular and/or

pulmonal comorbidity, palpable disease and postoperative bedrest. Additionally, the influence of

incision-type, sartorius transposition, saphenous vein sparing and skin removal was examined.

ResultsA total of 145 procedures was examined. One or more complications occurred in 104 (72%) of the

procedures; wound infection in 45%, seroma formation in 37% and skin flap problems in 26%. The

only statistically significant risk factor was age (odds ratio for one standard deviation increase: 1.46,

95%CI 1.01-2.14, p=0.05).

ConclusionsWound complication rates after ILND in melanoma patients are high. Age was the only predictor of

complications in this cohort; other previously identified risk factors could not be confirmed.

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IntroductionInguinal lymph node dissection (ILND) is considered the standard procedure in melanoma patients

when an involved sentinel node is found or in case of cytology confirmed palpable metastasis in the

groin. The procedure is considered high-risk in terms of postoperative wound complications such

as infection, seroma, skin edge necrosis and wound breakdown 1- 5. Identifying risk factors may offer

opportunities to reduce the risk of such morbidity. Previously found risk factors include patient-related

elements such as age, smoking habit, comorbidity and body mass index (BMI), but also surgery-related

factors like extent of dissection, disease-related factors like the number of involved lymph nodes, and

aspects of postoperative management 1-6. The presence and strength of the associations found in

these studies varies, prompting further research.

Current evidence suggests that centralization of surgical treatment in specialized hospitals with high

volumes of patients improves outcome for several types of cancer, particularly in terms of postop-

erative mortality and survival, although this has not yet been shown for lymph node dissection in

melanoma patients 7-9. Assuming that skill and postoperative management improve with experience,

one might also expect lower postoperative wound complication rates in high-volume hospitals.

Yet, the volume-outcome relationship for this outcome is not consistent in the literature for a range

of procedures 9-13.

As part of a quality improvement project for the surgical care of patients undergoing inguinal lymph

node dissection for melanoma, a historical cohort study was performed at The Netherlands Cancer

Institute, a specialized cancer hospital with a melanoma unit. The objective of this study was to assess

the frequency of early surgical wound complications after ILND and to identify patient-, disease- and

treatment-related risk factors for the occurrence of surgical wound complications.

MethodsSurgical technique of inguinal and additional iliacal/ pelvic lymphadenectomy and postoperative management.

Inguinal lymph node dissection, also referred to as ‘superficial groin dissection’, concerns the removal

of all fat and lymphatic tissue in the femoral triangle and anterior to the abdominal wall muscles.

Different types of incision may be used, dependent on the surgeon’s preferences; a longitudinal

incision or a single transverse incision for superficial dissection 1 – 2 cm caudal of the inguinal crease.

If skin is removed, an elliptical incision is used. The lateral border of the dissection is the sartorius

muscle, the medial boundary the adductor longus muscle and the proximal boundary an imaginary

line at least 5 cm above Poupart’s ligament. Iliac-obturator lymph node dissection, or ‘deep groin

dissection’ concerns removal of fat and lymphatic tissues along at least the external iliac vessels and

from the obturator fossa. In case of simultaneous superficial and deep groin dissection, a prolonged

longitudinal incision may be used, or an additional transverse incision is made, 5cm cranial of Poupart’s

ligament.

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If sartorius transposition is used, the muscle is detached from the anterior superior iliac spine, medially

rotated over the vessels and sutured to Poupart’s ligament. The greater saphenous vein can either be

ligated, or spared.

Prophylactic antibiotics are not routinely prescribed. One or two suction drains are placed in the

wound area. Bedrest is not routinely prescribed, but partial bedrest may be imposed, allowing only

for bathroom visits.

Data collection and patients

The retrospective chart review of our contemporary series included all patients with melanoma on

whom ILND was performed between 2003 and 2013. Collected data included patient and treatment

characteristics, as well as data on postoperative wound complications (within 30 days), using the

following definitions. Wound infection was defined as any inflammation of the wound that prompted

antibiotic treatment. Seroma formation was defined as any fluid collection in the wound that required

needle aspiration after initial removal of the drains. Skin flap problems included skin edge necrosis

and wound dehiscence. Complications were graded using the modified Clavien system 14-15. Wound

infections were classified as grade I when oral antibiotics were prescribed and grade II in case of

administration of intravenous antibiotics. Skin flap problems received grade I in case of conserv-

ative management, which included debridement at the bedside. Grade IIIa was assigned if negative

pressure wound therapy was initiated. Any complication that required intervention under general

anaesthesia was graded IIIb.

Statistics

Descriptive statistics on patient and treatment characteristics as well as complications are presented

using median and range for continuous data, and numbers and percentages for categorical data.

A risk model for surgical complications was developed with a composite, dichotomous outcome

variable (any vs. no postoperative complication). A pre-selection of predictor variables was made,

based on the current literature (See Table 5) and biological plausibility. These factors were BMI, age,

smoking history, diabetes mellitus, comorbidity other than diabetes mellitus, palpable disease and

days of postoperative bed rest 2-6.

Factors with 5% or less missing data were imputed with medians (continuous) or greatest prevalence

(discrete). Univariable associations with the occurrence of any grade wound complication were calcu-

lated for each of the predictor variables using binary logistic regression. Subsequently a multivariable

least absolute shrinkage and selection operator (LASSO) penalized logistic regression model was

employed to select the variables most strongly associated with the occurrence of any wound compli-

cation 16-18. BMI was retained throughout the selection since this factor was the most consistently

risk-associated factor in comparable, previous studies in melanoma patients 2-6.

Finally, the variables as identified in the penalized regression were entered into a non- penalized

multivariable logistic regression model. The odds ratios of this reduced model are reported with 95%

confidence intervals (95% CI), alongside the odds ratios of the penalized regression model as well as

the odds ratios of the full multivariable logistic model. The area under the receiver operator charac-

teristic curve (AUC) was calculated for the full and reduced model. The AUC reflects the probability

that a patient with observed complications has a higher predicted probability for complications than

19

a patient without observed complications, and as such serves as a measure for predictive value of the

model.

Additionally, we examined the possible association of type of incision, sartorius transposition, sparing

of the greater saphenous vein and removal of skin, using the same approach as described above, while

retaining all variables of the initial reduced model throughout the multivariable procedures.

To examine the influence of our definition of infection on the results, the analysis was repeated

excluding grade I infection from the composite endpoint, in a post-hoc analysis.

All p-values as reported are derived from two-sided tests.

ResultsComplication rates

A total number of 145 ILNDs in 138 patients were included in the study; seven patients underwent

ILND on both sides, but on separate dates. Patients had a median age of 56 years (range 15-84) and

43% was male. The majority of patients (82%) underwent both a superficial and deep dissection. Table

1 summarizes the characteristics of the patients and Table 2 the characteristics of the procedures

with and without subsequent early wound complications. One or more complications occurred in

104 (72%) of the procedures. The maximum experienced complication grade was grade I in 83 (57%)

procedures, grade II in eight (6%) and grade III in 13 (9%) procedures. Table 3 lists the number of

complications per type and grade.

Wound infection requiring oral antibiotics, intravenous antibiotics, or both was the most prevalent

complication (45%), followed by seroma formation requiring aspiration (37%), and skin flap problems

(26%). Table 2 lists complication frequencies by primary tumour, according to the modified Clavien

system.

Risk factors

In the univariable analysis, age was the only variable that was significantly associated with the occur-

rence of any wound complication (OR=1.49, 95%CI: 1.03-2.18, p=0.03) (Table 1). With BMI retained

throughout the variable selection, age was the only significantly associated factor in the multivariable

models (reduced model OR=1.46 for a one standard deviation (15.6 years) increase in age, 95%CI:

1.01-2.14, p=0.05). The LASSO model indicated that additionally a positive smoking history (reduced

model OR=1.83, 95%CI: 0.85-4.08, p=0.13) adds to the risk, but this association was not statistically

significant. No other variables under study were selected by the LASSO model. Table 4 lists multi-

variate associations for the full, penalized and reduced models. The AUCs of the full and reduced

models were 0.65 (95% CI: 0.55-0.75) and 0.64 (95% CI: 0.54-0.74) respectively, indicating limited

predictive abilities of the risk factors under investigation.

In the post-hoc analyses that excluded grade I wound infections from the composite endpoint,

smoking was rejected by the LASSO procedure, leaving age as the only selected variable. Despite

being selected by the LASSO procedure, age was no longer statistically significant at the 0.05 level in

the reduced model (OR 1.35, 95%CI 0.96-1.90, p= 0.08).

None of the additionally examined variables; type of incision, sartorius transposition, sparing of the

greater saphenous vein and removal of skin, were statistically significant in the univariable analysis and

nor were they selected in the additional multivariable LASSO model, with age, smoking history and

BMI retained (data not shown).

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Table 1: Patient characteristics divided by occurrence of (any grade) complications. P-values from univariable logistic regression on procedure level are reported, for variables under investigation only.

No complication

Any complication Total

N = 38 N = 100 N = 138 p-value

Gender

Female 23 ( 61%) 56 ( 56%) 79 ( 57%)

Male 15 ( 39%) 44 ( 44%) 59 ( 43%)

Agea 0.03

Median 51 58 56

(Range) (23 - 84) (15 - 84) (15 - 84)

Smoking Historya 0.12

No 25 ( 66%) 54 ( 54%) 79 ( 57%)

Past 4 ( 11%) 19 ( 19%) 23 ( 17%)

Current 8 ( 21%) 27 ( 27%) 35 ( 25%)

Missing 1 ( 3%) 0 ( 0%) 1 ( <1%)

BMIa 0.58

Median 24 26 25

(Range) (18 - 41) (17 - 43) (17 - 43)

Diabetes mellitusa 1.00

No 35 ( 92%) 92 ( 92%) 127 ( 92%)

Yes 3 ( 8%) 8 ( 8%) 11 ( 8%)

Cardiovascular or pulmonary comorbiditya 0.52

No 29 ( 76%) 82 ( 82%) 111 ( 80%)

Yes 9 ( 24%) 18 ( 18%) 27 ( 20%)

Number of ILNDs

1 34 ( 89%) 97 ( 97%) 131 ( 95%)

2 4 ( 11%) 3 ( 3%) 7 ( 5%)

aAt first operation for 7 patients.

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Table 2: Tumor/operation characteristics divided by occurrence of (any grade) early wound complications.P-values from univariable logistic regression on procedure level are reported, for variables under investigation only.

No complication

Any complication Total

N = 41 N = 104 N = 145 p-value

Type Of Incision

Longitudinal 23 ( 56%) 55 ( 53%) 78 ( 54%) ref

Single transverse 4 ( 10%) 14 ( 13%) 18 ( 12%) 0.92

Two transverse 13 ( 32%) 33 ( 32%) 46 ( 32%) 0.25

Other 1 ( 2%) 2 ( 2%) 3 ( 2%) 0.99

Sartorius Transposition 0.99

No 36 ( 88%) 91 ( 88%) 127 ( 88%)

Yes 4 ( 10%) 10 ( 10%) 14 ( 10%)

Missing 1 ( 2%) 3 ( 3%) 4 ( 3%)

Sparing Of The Greater Saphenous Vein

No 36 ( 88%) 89 ( 86%) 125 ( 86%) ref

Yes 1 ( 2%) 7 ( 7%) 8 ( 6%) 0.28

Missing 4 ( 10%) 8 ( 8%) 12 ( 8%) 0.13

Skin Removal 0.71

No 33 ( 80%) 82 ( 79%) 115 ( 79%)

Yes 6 ( 15%) 18 ( 17%) 24 ( 17%)

Missing 2 ( 5%) 4 ( 4%) 6 ( 4%)

Palpable Disease 0.70

No 13 ( 32%) 38 ( 37%) 51 ( 35%)

Yes 28 ( 68%) 66 ( 63%) 94 ( 65%)

Days of bed-rest 0.78

0 15 (37%) 43 (41%) 58(40%)

1 15 (37%) 32 (30%) 47 (33%)

2 2 (5%) 7 ( 7%) 9 (6%)

3 2 (5%) 12 (12%) 14 (10%)

4 2 (5%) 2 (2%) 4 (3%)

5 3 (7%) 8 (8%) 11 (8%)

7 1 (2%) 0 1(<1%)

Missing 1 (2%) 0 1(<1%)

Prophylactic antibiotics

No 33 (80%) 76 (73%) 109 (75%)

Yes 8 (20%) 28 (27%) 36 (25%)

Simultaneous Iliacal Dissection

No 5 ( 12%) 21 ( 20%) 26 ( 18%)

Yes 36 ( 88%) 83 ( 80%) 119 ( 82%)

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Table 3Frequencies, type and severity of complications after ILND per procedure, according to the modified Clavien system, in 237 ILNDs.

Grade I Grade II Grade IIIa Grade IIIB Total

Infection 47 (32%) 8 (6%) 10 (7%) 0 (0%) 65 (45%)

Skin flap problemsa 26 (18%) 0 (0%) 6 (4%) 6 (4%) 38 (26%)

Seroma formationa 53 (37%) 0 (0%) 0 (0%) 0 (0%) 53 (37%)

a Data on skin flap problems and seroma formation was lacking for one patient because of readmission elsewhere.

Table 4Multivariable analyses: reported are results from a full logistic regression model, the LASSO (L1) penalized model and the reduced logistic regression model.

Full modelPenalized

model Reduced model

Variable OR 95%CI p-value OR OR 95%CI p-value

Agea 1.53 1.04-2.30 0.04 1.24 1.46 1.01-2.14 0.05

Smoking history 2.01 0.91-4.64 0.09 1.29 1.83 0.85-4.08 0.13

BMI 1.14 0.77-1.72 0.53 1.11 1.11 0.76 – 1.67 0.60

Bedrest (days) 0.89 0.61-1.31 0.54 0

Diabetes Mellitus 0.74 0.18-3.70 0.68 0

Other comorbidity 0.91 0.36-2.46 0.85 0

Palpable disease 0.67 0.29-1.50 0.34 0

a The OR for age is reported for one standard deviation (15.6 years)

DiscussionThis study shows that for a complication-prone procedure such as ILND, complication rates can still

be high even in a specialized hospital with a high volume of patients. Of the risk factors under exami-

nation, only age had a statistically significant association with the occurrence of complications in this

cohort.

Complication rates

The complication rate in our series is largely in accordance with the findings of other recently published

studies, with the exception of a higher wound infection rate. A recent article summarised the results of

eleven studies on inguinal lymph node dissection in melanoma patients performed between 1992 and

2008. In these studies wound necrosis occurred in 3% to 26% of cases, seroma formation in 5% to 46%

and cellulitis or wound infection in 9% to 30% 4. In another recent study, the overall complication rate

for infection or wound dehiscence was only 13%, but this study did not include seroma and used very

strict definitions of complications 19. The higher wound infection rate found in our study may be due to

the chosen criterion for wound infection: any inflammation for which antibiotics were prescribed also

in cases without microbiological confirmation of infection. It is possible that this choice overestimates

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the true number of infections, but it does reflect the actual rate of deviation from the normal postop-

erative trajectory. Conversely, the true amount of infections may be underestimated when microbi-

ological confirmation is used as a criterion, if experienced clinicians prescribe antibiotics correctly,

but without obtaining a wound culture. A prospective study that used the same criterion for infection

after ILND for melanoma found an even higher overall infection rate of 57% 5. This could indicate that

besides the choice of definition, underreporting in medical files accounts for the lower infection rates

found in retrospective studies.

Currently established Dutch guidelines on the quality of oncological care require a hospital to perform

a minimum of ten procedures per year for deep lymphnode dissections in melanoma patients. We

believe that the high complication rates associated with ILND provide an argument for extending this

requirement to superficial lymph node dissections. A high volume hospital will have the opportunity

to develop high quality of wound care for these patients, and can systematically try to minimize the

risk of postoperative morbidity. Moreover, the effect of alterations to surgical care and nursing on the

medical outcome can only be reliably studied with a sufficient caseload.

Risk factor analysis

Few studies have used multivariable models to identify risk factors for early surgical complications

after ILND in melanoma patients 2-6. Modelling risk factors in relatively small datasets comes with a

risk of type-I errors, due to overfitting and multiple testing. To account for this, we used two staged

approach of testing associations. Initially, we considered the evidence from available studies that

used a comparable outcome variable, to construct an initial set of variables of interest. Secondly

we performed regression analyses using these variables to assess their potential importance. Of

the variables assessed in the literature, BMI was the most consistently factor associated with com-

plications, and it was therefore forced entered in the subsequent multivariable LASSO regressions.

The LASSO procedure performs variable selection by applying shrinkage to the coefficients of the full

model in such a way that some coefficients are shrunk exactly to zero, instead of by stepwise rejecting

of statistically non-significant factors. This method has been recommended for small datasets, as it

reduces the chance of overfitting the data 16-18.

We observed an increased risk in patients with a history of smoking in our series. While smoking was

retained by the LASSO procedure, the relationship was not statistically significant at the 0.05 level.

Although this could be the result of insufficient statistical power, previous studies comparable to ours

also did not find a statistically significant relationship 4-6. Also, smoking was not retained by the LASSO

model in the post-hoc analysis after excluding grade I infections from the composite endpoint. This

could indicate that smoking history is not a risk factor for early wound complications, but it should be

noted that assessing the exact amount of exposure to smoking (e.g. in terms of pack-years) is difficult

in general and particularly problematic through a retrospective chart review. Therefore, the finding

may be subject to information bias.

In the exploratory analysis of the type of incision, sartorius transposition, sparing of the greater

saphenous vein and removal of skin, none of the variables were associated with complications in this

cohort. This is consistent with findings of a previous study on the risk of major wound complications 2.

On the other hand, in a large observational study sartorius transposition was associated with lower risk

of wound complications, but only after accounting for operative time 19. Conversely, sartorius transpo-

sition has been associated with elevated risk of wound complications after ILND for penile cancer 20.

While the finding in that study may have been confounded by indication, a randomized controlled trial

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in patients with vulvar cancer showed that sartorius transposition did not limit overall postoperative

morbidity but did increase seroma formation 21. Moreover, sartorius transposition may increase the

risk of persistent lymphoedema 22. Overall, current evidence indicates that sartorius transposition

should not be performed routinely.

The influence of transverse versus longitudinal incisions has not been previously studied. Based on our

findings, it remains a matter of personal preference without consequence for postoperative morbidity.

Limitations and strengths

The retrospective character of the study may have induced bias, in particular information bias, despite

the fact that the data were gathered using prospectively documented medical files. The use of a

composite endpoint (any complication) precludes the identification of risk factors that are associated

with a particular type of complication but not with another. The choice for a composite endpoint is

justified, because the number of events in our cohort did not warrant multiple analyses for separate

outcomes, as this would have unduly increased the chance of type-I errors.

The strengths of our study are the relatively large number of patients for a rare procedure such as

ILND, and the systematic and multivariable approach to identification of risk factors.

Future perspectives

The limited predictive value of the multivariable models indicates that there may be other, as yet

unknown factors that influence the risk of early postoperative wound complications. Therefore, and

keeping in mind the inconsistent nature of the evidence to date, future studies are required to explore

other possible risk factors as well as confirming the current results. Detailed and uniform prospective

registration of risk factors, procedures and outcome for all patients undergoing ILND would greatly

facilitate research on quality improvement of surgical and peri-operative care for this procedure.

A registration system to that end is currently being implemented in our institute. Such a system should

preferably be multi-centred to support surgical audits, comparable to those currently implemented

for colorectal cancer resection in several European countries 23-24.

ConclusionILND in melanoma patients is associated with a high complication rate (72% in this study), even in a

high volume, specialized cancer hospital. Age was the only statistically significant predictor for the

occurrence of wound complications in this cohort, although smoking history added to the risk. A risk

model containing these variables has only limited predictive value for the occurrence of early wound

complications, warranting further research into risk factors for early wound complications after ILND.

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Table 5 Risk factors for early wound complication after ILND in melanoma patients as reported in the recent literature. Listed are results from univariable analyses (UV) and multivariable analyses (MV), of studies using a composite endpoint (any complication). 0 = no significant association found (p>0.05), + = risk factor, - = protective factor

Author Year

Serpella20033

Sabelb20072

Poos20094

Chang20105

Wevers20126

Bartlettb

201319Current study

Patient factors UV MV UV MV UV MV UV MV UV MV UV MV UV MVAge 0 0 + + 0 + + + + +Gender 0 0 0 0 0White race 0BMI + + 0 + + 0 0 + 0 0Smoking 0 0 0 0 0Cardiovascular/ pulmonal comorbidity 0 0

DM 0 0 + 0 0Steroid use 0History of bleeding disorder 0Preoperative albumin 0

Comorbidity (unspecified) +c 0 0d + 0

Procedure Additional iliacal dissection 0 0 0 0Sparing VSM 0 0 0Type of incision 0 0 0Skin sparing 0 0Sartorius transposition 0 0 - 0 0Surgical procedure (unspecified) 0

Operative time 0 0 0Surgeon (fellow or staff) 0 0Pathology Prior exision biopsy 0Diagnosis by cytology 0Number of removed nodes 0Number of positive nodes 0 0Median size largest node 0 +Macroscopic (palpable) disease 0 + + 0 0 0 0 0

Tumour thickness 0Nodular/superficial spreading 0Disease Stage 0Extracapsular growth 0Time to diagnosisPostoperative management 0Bed rest - - 0 +/0e 0 0Drain Time 0Number of drains 0

a This study included inguinal, axillary and neck lymph node dissection.Results were adjusted for dissected regionb This study did not include seroma formation in the composite endpointc comorbidity included diabetes, cardiovascular diseases and chronic obstructive pulmonary diseasesd comorbidity was unspecified, but included tobacco use and diabetese Bedrest for 10 days without splint was a risk factor when compared to 10 days bedrest with Bohler Braun splint bedrest for 5 days without splint was not.

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3. Serpell JW, Carne PWG, Bailey M. Radical lymph node dissection for melanoma. ANZ J Surg 2003;73:294-9.

4. Poos HPAM, Kruijff S, Bastiaannet E, van Ginkel RJ, Hoekstra HJ. Therapeutic groin dissection for melanoma: Risk factors for short term morbidity. Eur J Surg Oncol 2009; 35:877-83.

5. Chang SB, Askew RLA, Xing Y, et al. Prospective assessment of postoperative complications and associated costs following inguinal lymph node dissection (ILND) in melanoma patients. Ann Surg Oncol 2010;17:2764-72.

6. Wevers KP, Poos HPAM, van Ginkel RJ, van Etten B, Hoekstra HJ. Early mobilization after ilio-in-guinal lymph node dissection for melanoma does not increase the wound complication rate. Eur J Surg Oncol 2012; 39:185-90

7. Gooiker GA, van Gijn W, Post PN, van de Velde CJH, Tollenaar RAEM, Wouters MWJM. A systematic review and meta-analysis of the volume-outcome relationship n the surgical treatment of breast cancer. Are breast cancer patients better of with a high volume provider? Eur J Surg Oncol 2010;36:S27-S35.

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9. Wouters MWJM, Gooiker GA, van Sandick JW, Tollenaar RAEM. The volume-outcome relation in the surgical treatment of esophageal cancer. Cancer 2011; 118:1754-63

10. Yasunaga H, Matsuyama Y, Ohe K. Effects of hospital and surgeon volumes on operating times, postoperative complications, and length of stay following laparoscopic colectomy. Surg Today 2009; 39:955-61.

11. Nugent E, Neary P. Rectal cancer surgery: volume-outcome analysis. Int J Colorectal Dis 2010; 25:1389-96.

12. Wilt TJ, Shamliyan TA, Taylor BC, MacDonald R, Kane RL. Association Between Hospital and Surgeon Radical Prostatectomy Volume and Patient Outcomes: A Systematic Review. J Urol 2008; 180:820-9.

13. Barocas DA, Mitchell R, Chang SS, Cookson MS. Impact of surgeon and hospital volume on outcomes of radical prostatectomy. Urol Oncol 2011; 28:243-50.

14. Clavien PA, Sanabria JR, Strasberg SM. Proposed classification of complications of surgery with examples of utility in cholecystectomy. Surgery 1992; 111:518-26.

15. Dindo D, Demartines N, Clavien PA. Classification of Surgical Complications: A New Proposal With Evaluation in a Cohort of 6336 Patients and Results of a Survey. Ann Surg 2004; 240:205-13.

16. Steyerberg EW, Eijkemans MJ, Harrell FE, Habbema JD. Prognostic modelling with logistic regression analysis: a comparison of selection and estimation methods in small data sets. Stat Med 2000; 19:1059-79.

17. Steyerberg EW, Eijkemans MJ, HAbbema JD. Stepwise selection in small data sets: a simulation study of bias in logistic regression analysis. J Clin Epidemiol 1999; 52:935- 42.

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18. Steyerberg EW, Eijkemans MJ, Harrell FE Jr, HAbbema JD. Prognostic modeling with logistic regression analysis: in search of a sensible strategy in small data sets. Med Decis Making 2001; 21:45-56.

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20. Stuiver MM, Djajadiningrat RS, Graafland NM, Vincent AD, Lucas C, Horenblas S. Early Wound Complications After Inguinal Lymphadenectomy in Penile Cancer: A Historical Cohort Study and Risk-factor Analysis. Eur Urol 2013; 64:486-92.

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23. van Gijn W, van den Broek CBM, Mroczkowski P, et al. The EURECCA project: Data items scored by European colorectal canceraudit registries. Eur J Surg Oncol 2012; 38:467–71

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CHAPTER 3Early wound complications after inguinal lymphadenectomy in penile cancer, a historical cohort study and risk factor analysis.

Martijn M. Stuiver, MSc a;b

Rosa S. Djajadiningrat, MD c

Niels M. Graafland, PhDMD c

Andrew D. Vincent, PhD d

Cees Lucas, PhD b

Simon Horenblas, PhD, MD, FEBU c

a The Netherlands Cancer Institute, Department of Physiotherapyb Academic Medical Centre, University of Amsterdam, Department of Clinical

Epidemiology, Biostatistics and Bioinformaticsc The Netherlands Cancer Institute, Dpt of Urologyd The Netherlands Cancer Institute, Dpt of Biostatistics

Published in European Urology 2013 Sep;64(3):486–92.

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ABSTRACTBackgroundComplication rates after inguinal lymph node dissection (ILND) are high. Risk factors for early wound

complications after ILND in patients with penile carcinoma have not yet been studied.

ObjectivesTo assess the frequency of early wound complications in a contemporary series and to identify clinical

risk factors for early wound complications after ILND for penile carcinoma.

Design, settings and participantsWe evaluated 237 ILNDs in 163 patients with penile cancer treated between 2003 and 2012 at the

Netherlands Cancer Institute.

Outcome measurements and Statistical AnalysisWe assessed the occurrence of wound infection, skin flap problems and seroma formation, and

graded complications through the modified Clavien system. Univariable and multivariable mixed

effects penalized logistic regression were used to identify clinical risk factors for occurrence of any

complication (≥ grade 1) and moderate to severe complications (≥ grade 2).

Results and limitationsOne or more complications occurred in 58% of the procedures, of which 10% were severe. Wound

infection occurred in 43%, seroma formation in 24% and skinflap problems in 16%.

Palpable disease was the only associated factor for ≥grade 1 complications in the univariable analysis

(OR=0.43, p=0.02). In the multivariable model after penalization, no statistically significant risk factors

remained.

Univariable associations for ≥grade 2 complications were present for Body Mass Index (OR=1.7

for IQR (5.8) change in BMI, p=0.05) and sartorius muscle transposition (OR=2.6, p=0.04). In the

reduced multivariable model, the OR for sartorius muscle transposition was 2.1 (p=0.06) and for BMI

1.8 (p=0.03). Additionally, bilateral dissection approached significance in the multivariable model

(OR=2.2, p=0.06). This study is limited by its observational nature.

ConclusionWound complication rates after ILND are high in this cohort. BMI, sartorius muscle transposition and

bilateral dissection were the factors most strongly associated with the occurrence of ≥grade 2 wound

complications.

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IntroductionInguinal lymph node dissection (ILND) is performed in penile cancer patients at high risk for lymph

node metastases or in patients with established regional lymph node metastases. The ILND can also

be performed after a tumour positive sentinel node procedure or following tumour positive fine

needle aspiration cytology (FNAC). The ILND is carried out simultaneously with the removal of the

primary tumour or as an elective procedure. In case of pelvic lymph node involvement or in patients at

high risk for pelvic involvement, simultaneous pelvic node dissection (PLND) is performed.

ILND is associated with a high morbidity rate. Short-term surgical complications include wound

infection, seroma formation, skin flap problems and wound breakdown. The reported incidence of

early postoperative wound complications varies strongly in the current literature, but can be as high

as 77% 1-6. Over a longer period, lymphoedema of the leg and/ or genital area may occur in varying

degrees 2,6-9.

Previous studies in melanoma patients and vulvar cancer patients have tried to identify clinical

risk factors for the occurrence of surgical complications after ILND 1,4,5,7,10. To our knowledge, such

attempts have not yet been made explicitly in patients with penile carcinoma, although comparisons

have been made of complication rates in prophylactic versus therapeutic and palliative dissection 11,

and in radical versus modified ILND 12.

Risk factors for any early surgical complication after ILND, as reported in the surgical literature in

patients with melanoma or vulvar cancer are age 1,10, diabetes 10 and other comorbidity 1, body mass

index (BMI) 1,7, and drain production 10. However, the presence of each risk factor is inconsistent,

varying between studies 1,7,10.

Identification of risk factors for wound complications is clinically relevant. Therefore, we performed an

historical cohort study, with two objectives:

1. To assess the frequency of early surgical wound complications after groin

dissection for penile carcinoma;

2. To identify patient, tumour and treatment characteristics as risk factors for the

occurrence of early wound complications after ILND.

MethodsData collection

We performed a chart review, of all patients with penile cancer and ILND between 2003 and 2012

at the Netherlands Cancer Institute, a high-volume, specialized cancer hospital. Patients in whom

the ILND was part of extensive resection that involved reconstructive surgery with myocutaneous

flaps were excluded. We collected patient characteristics, tumour type and treatment characteristics

and data on early surgical wound complications. Early surgical wound complications were defined as

complications occurring within 30 days after the operation. The complications of interest were wound

infection, skin flap problems and seroma formation.

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Definition and grading of outcome variables

All complications were strictly defined and graded in concordance with the modified Clavien system

that allows for reporting complications of general surgery in a uniform manner 13,14.

Complications were defined as follows:

Wound infection: Any occurrence of inflammation for which oral (grade I) or intravenous (grade II)

antibiotics were prescribed.

Skin flap problems: Any wound dehiscence (including wounds that were opened) or skin edge necrosis.

Skin flap problems were classified as grade I if no intervention other than wound care was necessary.

Skin flap problems that required surgical intervention outside the operating room or readmission to

the hospital were classified as grade II.

Seroma formation: Serous fluid collection that developed under the skin flap that required needle

aspiration (grade I) or reopening of the wound (grade II) after removal of the drain.

Any complication that led to initiation of negative pressure wound therapy was qualified as grade IIIa.

Any complication that required surgical re-intervention in the operating room under general anaes-

thesia was graded as IIIB.

Complications were graded by two researchers independently (MS and RD) and any discrepancies

were resolved in consensus.

Surgical technique of inguinal and additional pelvic lymphadenectomy

The technique of the inguinal lymphadenectomy as performed in all patients has been described in

detail 15,16. Briefly, all connective, fat and lymphatic tissue is removed through an incision parallel and

2 cm inferior to the inguinal crease between the following boundaries: proximal boundary: inguinal

ligament; distal boundary: the adductor longus muscle at the crossing with the sartorius muscle;

medial boundary: adductor muscle and the lateral margin: sartorius muscle. The floor of the dissection

consists of the fascia lata, pectineus muscle and the ventral surface of the femoral vein and artery.

In case of former dynamic sentinel node biopsy or skin involvement, the biopsy scar or involved

skin is removed with an elliptical incision. A separate infra-umbilical midline incision is used for the

PLND . This consists of removal of all lymphatic tissue between the following boundaries: proximal:

bifurcation of the aorta, lateral: genitofemoral nerve, medial: prostate, bladder and the internal iliac

artery, and lateral: the pelvic floor. In rare cases, en bloc removal of the primary tumour and bilateral

ILND is performed. Prophylactic antibiotics were not always routinely used, but have been part of

the standard protocols in recent years. Suction drains are placed in the dissected area and generally

removed after less than 50cc production per 24 hours or after maximally 15 days.

Statistics

We report the medians and ranges for continuous data, and frequencies and percentages for nominal

data.

For the assessment of risk factors, a pre-selection of variables was based on biological plausibility

and/or a previously reported association with the the occurrence of complications. This initial set of

variables included age, BMI, number of removed lymph nodes, number of tumour-positive lymph

nodes, smoking status, type II diabetes, bilateral dissection in a single procedure, simultaneous PLND,

indication for the ILND, concomitant removal of skin, transposition of the sartorius muscle, sparing of

the greater saphenous vein and continuation of prophylactic antibiotics.

33

The association between clinical factors and occurrence of complications, both any complication

(grade 1+) and moderate to severe complications (grade 2+) were assessed using univariable and

multivariable mixed effects logistic regression. Mixed effects regression was used to account for

within-patient correlations.

The multivariable analysis consisted of LASSO* (L1) penalized logistic mixed effects regression 17,

with k-fold cross validated likelihood (k=40) used to determine the optimal penalty parameter 18,19.

Variables with non-zero coefficients were subsequently entered into a (non-penalized) mixed effects

logistic regression model for comparison with the univariable regression results. In all mixed effects

models random intercepts were included per patient.

Numeric variables were centered and scaled by subtracting the mean and dividing by the standard

deviation. Missing data were imputed using medians for numeric variables and largest subgroup

for factors. Odds ratios for continuous data are reported for a change of one inter-quartile range.

Addtionally, we performed a sensitivity analysis using the same procedure with infection as the

response variable.

ResultsComplication rates

Between 2003 and 2012, 171 consecutively treated patients were identified who underwent an ILND.

Eight patients were excluded due to additional reconstructive surgery. Furthermore 73 patients had

a bilateral dissection (of which 45 in a single procedure) and one patient had three procedures due to

a recurrence. Thus, the total number of ILNDs was 237 ILNDs from 163 patients. Table 1 summarizes

the patient characteristics.

One or more wound complications occurred in 58% of the procedures, with severe (grade III) compli-

cations occurring in 10%. Wound infection requiring oral antibiotics (23%), intravenous antibiotics or

both (20%) was the most prevalent complication. This was followed by seroma formation (24%) and

skin flap problems (16%). Two complications after a single procedure occurred in 22%, and three in

less than 1%. Table 2 presents an overview of frequencies and severity of all early wound complica-

tions according to the modified Clavien system.

Risk factors

In the univariable analysis with any complication ≥ grade 1 as the outcome variable, the only statis-

tically significant associated factor was palpable disease (OR=0.43, p=0.02) (Table 3). However, no

predictors including palpable disease were retained by the LASSO regression.

In the analysis of grade 2 or higher complications, BMI (OR=1.7, p=0.05) and sartorius muscle

transposition (OR=2.6, p=0.04) were statistically significantly associated in the univariable analysis

(Table 3). The strength of both of these associations remained largely unchanged in the reduced

multivariable model (Table 4). The influence of BMI appeared stronger (OR=1.8, p=0.03), while the

influence of sartorius muscle transposition was somewhat attenuated and no longer statistically

significant at the 0.05 level (OR=2.1, p=0.06). In addition, bilateral dissection approached significance

in the multivariable regression (OR 2.2, p=0.06). In the sensitivity analysis with infection as the outcome

variable, the factor with the strongest association was palpable disease (OR 0.49, p=0.03) , while the

trend for BMI remained (OR 1.42, p=0.09) (Table 5).

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*Least Absolute Shrinkage and Selection Operator

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Table 1 Patient and procedure characteristics

Patient Characteristics a

Total Number of dissections 163

Median age in years (min-max) 66 (33 - 91)

Median BMI (min-max) 26.8 (17.0 –45.2)

Obese (BMI>30) 39 (24%)

Smoking 43 (26%)

Diabetes Mellitus 22 (14%)

Bilateral dissection 45 (28%)

Surgical/Tumour Characteristics b

N 237

Recurrent tumour 40 (17%)

Tumour size

pT0 1 (<1%)

pT1a 13 ( 5%)

pT1b 19 ( 8%)

pT2 162 (68%)

pT3 34 (14%)

pT4 4 ( 2%)

pTx 4 ( 2%)

Nodal status

pN0 10 ( 4%)

pN1 64 (27%)

pN2 55 (23%)

pN3 108 (46%)

Indication lymph node dissection

Positive SN 76 (32%)

Palpable disease 85 (36%)

Positive FNAC 67 (28%)

Otherc/not specified 9 ( 4%)

Simultaneous pelvic dissection 58 (25%)

Median number of lymph nodes removed (min – max) 9 (1 – 25)

Median number of positive lymph nodes (min-max) 1 (0 – 20)

Skin sparing 153 (65%)d

Sartorius muscle transposition 94 (40%)e

Sparing of greater saphenous vein 135 (57%)f

Prophylactic antibiotics 166 (70%)

Median duration of drainage (min – max) 11 (1 – 57)

Median duration of hospitalization (min – max) 9 (1 - 62)

a percentages in the upper part of the table are relative to the number of patientsb percentages in the lower part of the table are relative to the number of procedures c sentinal node procedures in which the sentinal node could not be identifiedd unknown in 13 cases | e unknown in 6 cases | f unknown in 17 cases

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Table 2 Frequencies, type and severity of complications after ILND per procedure, according to the modified Clavien system, N=237

Wound complications Grade I Grade II Grade IIIa Grade IIIB TotalInfection 54 (23 %) 43 (18%) 1 (<1%) 4 ( 2%) 102 (43%)

Skin flap problemsa 9 ( 4%) 8 ( 3%) 14 ( 6%) 6 ( 3%) 37 (16%)

Seroma formationa 53 (22%) 2 ( 1%) 0 (0%) 1 (<1%) 56 (24%)

a Data on skin flap problems and seroma formation was lacking for one patient because of readmission elsewhere.

Table 3Univariable asscociations of the risk of any complication (grade ≥ 1) and moderate to severe (grade ≥ 2) complications

grade≥1 grade ≥2

OR 95%CI p-value OR 95%CI p-value

Age (at surgery)a 1.38 (0.84 - 2.27) 0.24 1.19 (0.68 - 2.10) 0.56

Smoking status 1.43 (0.65 - 3.16) 0.41 1.41 (0.59 - 3.34) 0.46

Diabetes Mellitus type 2 0.41 (0.14 - 1.17) 0.12 1.48 (0.49 - 4.44) 0.51

BMIb 1.30 (0.82 - 2.08) 0.30 1.66 (1.02 - 2.70) 0.05

Bilateral ILND 1.80 (0.85 - 3.81) 0.15 2.11 (0.91 - 4.87) 0.09

Pelvic Dissection 1.21 (0.55 - 2.65) 0.66 2.29 (0.92 - 5.66) 0.11

Removed nodesc 0.65 (0.43 - 1.00) 0.06 0.83 (0.50 - 1.38) 0.48

Number of positive nodes 0.97 (0.81 - 1.16) 0.73 1.06 (0.89 - 1.28) 0.54

Palpable disease 0.43 (0.22 - 0.84) 0.02 0.65 (0.30 - 1.44) 0.30

Removing skin 0.63 (0.31 - 1.28) 0.24 2.48 (0.22 - 27.4) 0.34

Sartorius muscle transposition 0.80 (0.40 - 1.63) 0.58 2.64 (1.06 - 6.60) 0.04

Sparing of the greater saphenous vein 1.11 (0.55 - 2.26) 0.78 1.94 (0.27 -14.05) 0.54

Continuation of prophylactic antibiotics 0.55 (0.26 - 1.19) 0.16 0.70 (0.32 - 1.56) 0.41

a OR is reported for a change in age equivalent to the interquartile range: 18b The OR is reported for a change in BMI equivalent to the interquartile range: 5.8c The OR is reported for number of removed lymph nodes equivalent to the interquartile range: 5.0

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Table 4Multivariate models of the risk of moderate to severe complications (grade ≥2). Reported are estimates from a penalized (LASSO) logistic mixed effects regression and an unpenalized logistic mixed effects regression, the latter only including factors which had non-zero coefficients in the LASSO regression.

Penalized model Reduced modelOR 95%CI p-value OR 95%CI p-value

Age (first surgery) 1

Body Mass Indexa 1.58 (1.01 - 2.48) 0.05 1.76 (1.04 - 2.96) 0.03

Number of removed nodes 1

Number of positive nodes 1

Smoking status 1.39 (0.65 - 2.95) 0.40 1.49 (0.62 - 3.59) 0.37

Diabetes Mellitus type 2 1

Bilateral ILND 1.8 (0.89 - 3.64) 0.10 2.17 (0.96 - 4.95) 0.06

Concomitant PLND 1

Palpable disease 0.61 (0.3 - 1.26) 0.18 0.55 (0.24 - 1.25) 0.15

Removing skin 1

Sartorius muscle transposition 1.81 (0.91 - 3.59) 0.09 2.12 (0.97 - 4.63) 0.06

Sparing of the greater saphenous vein 1.56 (0.76 - 3.2) 0.23 1.75 (0.77 – 4.00) 0.18

Continuation of prophylactic antibiotics 0.71 (0.34 - 1.48) 0.36 0.67 (0.29 - 1.55) 0.35

a The OR is reported for a change in BMI equivalent to the interquartile range: 5.8

Table 5Multivariate models of the risk of any grade wound infection. Reported are estimates from a penalized (LASSO) logistic mixed effects regression and an unpenalized logistic mixed effects regression, the latter only including factors which had non-zero coefficients in the LASSO regression.

Penalized model Reduced modelOR 95%CI p-value OR 95%CI p-value

Age (first surgery) 1

Body Mass Indexa 1.38 (0.93 – 2.04) 0.11 1.42 (0.95 – 2.13) 0.09

Number of removed nodes 0.82 (0.60 – 1.11) 0.20 0.78 (0.57 – 1.06) 0.12

Number of positive nodes 1

Smoking status 1

Diabetes Mellitus type 2 1

Bilateral ILND 1

Concomitant PLND 1

Palpable disease 0.53 (0.29 – 0.98) 0.04 0.49 (0.26-0.91) 0.03

Removing skin 1

Sartorius muscle transposition 1

Sparing of the greater saphenous vein 1

Continuation of prophylactic antibiotics 0.80 (0.42-1.53) 0.49 0.78 (0.40 – 1.49) 0.45

a The OR is reported for a change in BMI equivalent to the interquartile range: 5.8

37

DiscussionComplication rates

This study shows that even in a high-volume specialized centre, complication rates of ILND in penile

carcinoma patients can be high. Our findings contrast with those of recently published studies in

patients with penile cancer. Overall complication rates in contemporary series (2002 – 2008) were

between 49% and 57% when including lymphoedema. Short term morbidity in these studies was

limited with infection rates between 7.5% and 10% and wound breakdown and necrosis rates

between 2.5% and 11% 2. One explanation for this discrepancy could be that the complication rates

in these retrospective studies were underestimated, due to of underreporting in the medical files.

An alternative explanation is that we used a broad definition of infection; any inflammation for which

antibiotics were prescribed, also in cases without microbiological confirmation. This may have caused

an overestimation of infection rate, if antibiotics were prescribed for patients in whom redness or

swelling was falsely attributed to infection.

Risk factors

Previous studies have attempted to determine the risk factors for early surgical complications after

ILND in melanoma and vulvar cancer patients 1,4,5,7,10 This is the first study to identify clinical risk factors

for surgical complication following ILND in patients with penile cancer.

We used a LASSO procedure to select variables with the strongest association with complications.

This procedure selects variables for the final model by applying shrinkage on the regression coeffi-

cients of the full model, to such an extent that some coefficients are shrunk to zero. This method of

variable selection is less prone to overfitting than conventional stepwise backward or forward entry

selection procedures, and has been recommended for use in relatively small datasets 20,21.

The odds of developing a complication of grade ≥2 increased by a factor 1.8 per 5.8 point change in

BMI, implying that the risk of complications in overweight and obese patients is substantially higher

compared to patients with normal weight. Obesity has been associated with postoperative complica-

tions in ILND and other surgical patients previously 1,22. It is hypothesized that increased susceptibility

to surgical site infections in obese patients results from tissue hypoperfusion, which in turn may lead

to greater risk of ischemia or necrosis and suboptimal neutrophil oxidative killing 22.

Our finding that sartorius muscle transposition is associated with increased risk for complications

should be interpreted with caution, considering the observational nature of the study. Particularly,

confounding by indication may have occurred. The purpose of performing sartorius muscle transpo-

sition is to cover femoral vessels and limit postoperative complications and morbidity. Consequently,

it may have been performed electively in patients who were already judged by the surgeon to be at

high risk for complications on other grounds. Nevertheless, a randomized controlled trial examining

the effect of transposition of the sartorius muscle on morbidity after ILND in patients with vulvar

cancer showed no favourable effects and a possible negative impact on seroma formation in the

intervention group 23. Also, transposition of the sartorius muscle has been associated with higher

incidence of persisting lymphoedema 9. Based on these findings, the harm of the procedure seems to

outweigh possible benefits and it should not be carried out routinely.

Smoking status did not seem to increase the risk of complications in our study. Current non-smokers

may have an accumulated risk of past smoking behaviour. Because packyears were missing for a

substantial number of patients the influence of smoking history could not be fully explored. Also,

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information bias may have occurred with regard to smoking status, due to inadequate registration in

the medical files.

A modified procedure with limited dissection and sparing of the greater saphenous vein in patients

with penile carcinoma has been associated with a morbidity rate of 7% 12. In patients with vulvar

cancer, sparing of the saphenous vein has also been associated with less cellulitis and wound

breakdown, but not with less seroma formation 24-26. Saphenous vein sparing did not emerge as a

predictive factor in our model. However, since preservation of the greater saphenous vein has also

consistently been associated with lower risk of chronic lymphoedema 8, sparing of the vein would still

be recommendable, whenever this is deemed safe oncologically.

Although most of the identified risk factors are non-modifiable, they still have clinical relevance. Patients

who, based on these risk factors, are identified as complication-prone might benefit from alternative

surgical procedures such as minimally invasive videoscopic dissection or robot-assisted procedures.

These techniques have not yet been widely used, but initial experiences in non- randomized trials

show favourable results with respect to complication rates 27-29.

Limitations

Some important limitations of this study should be noted. The investigators that retrieved the risk

factors were not blinded for the outcome. However, all information was retrieved from prospectively

documented medical files so bias due to lack of blinding is unlikely. As in any chart-review study,

there is a risk of information bias as a result of suboptimal reporting in the medical files, in particular

misclassification with regard to the presence of predictor variables. The sample size and event rate of

the study limited the number of variables that could be fully examined. We used a composite

endpoint to improve statistical efficiency. This comes at the cost of losing the ability to identify risk

factors associated with one complication, but not with another. Therefore, we performed a sensi-

tivity analysis with infection as the outcome variable, using the same variables as possible predictors.

From this analysis, it seems that palpable disease is more associated with (reduced) wound infection

risk, while BMI and particularly sartorius transposition and DM may be more related to the other

complications.

Future perspectives

Despite its limitations, this is the largest study of complications after ILND in a consecutive series of

patients with penile carcinoma to date. Confirmation of our findings in future studies is necessary to

validate our results, before attempts can be made to develop a clinical prediction rule. Moreover, given

the limited number of predictors that were identified in this study, other possible risk factors should

be explored in future studies, such as ASA score or performance status, prior SN and concomitant

removal of the primary tumour. Future studies would benefit from detailed, prospective registration

of risk factors and outcome.

ConclusionInguinal lymph node dissection is associated with a high wound complication rate in patients with

penile carcinoma, even in a high volume, specialized cancer hospital. In this cohort BMI, transposition

of the sartorius muscle and bilateral dissection were the factors most strongly associated with the

occurrence of moderate to severe wound complications.

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20. Steyerberg EW, Eijkemans MJ, Habbema JD. Stepwise selection in small data sets: a simulation study of bias in logistic regression analysis. J Clin Epidemiol 1999 52:935-42.

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23. Judson PL, Jonson AL, Paley PJ, et al. A prospective, randomized study analyzing sartorius trans-position following inguinal-femoral lymphadenectomy. Gynecol Oncol 2004; 95:226-30.

24. Dardarian TS, Gray HJ, Morgan MA, Rubin SC, Randall TC. Saphenous vein sparing during inguinal lymphadenectomy to reduce morbidity in patients with vulvar carcinoma. Gynecol Oncol 2006; 101:140-2.

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CHAPTER 4No evidence of benefit from class-II compression stockings in the prevention of lower-limb lymphoe-dema after inguinal lymph node dissection; Results of a randomized controlled trial

M. M. Stuiver, MSc physical therapist, clinical epidemiologist 1,8

J. D. de Rooij, MSc physical therapist, epidemiologist 6

C. Lucas PhD, physical therapist, clinical epidemiologist 8

O. E. Nieweg, M.D., Ph., surgeon 2

S. Horenblas, M.D., PhD, urologist 3

A. N.van Geel, M.D., PhD, surgical oncologist 7

M. van Beurden, M.D., PhD, gynaecologic oncologist 4

N. K. Aaronson PhD, behavioural scientist, health outcomes researcher5

Departments of 1. The Netherlands Cancer Institute, Department of Physiotherapy2. The Netherlands Cancer Institute, Department of Surgical Oncology3. The Netherlands Cancer Institute, Department of Urology 4. The Netherlands Cancer Institute, Center of gynecological oncology Amsterdam, and 5. The Netherlands Cancer Institute, Division of Psychosocial Research and Epidemiology, 6. Erasmus University Medical Centre-Daniel den Hoed, Department

of Rehabilitation Medicine and Physical therapy, 7. Erasmus University Medical Centre-Daniel den Hoed, Department of Surgical Oncology8. Academic Medical Center, University of Amsterdam, Department of

Clinical Epidemiology, Biostatistics and Bioinformatics

Published in Lymphology 2013; 3:120-131

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ABSTRACTBackground and ObjectiveGraduated compression stockings have been advocated for prevention of lymphoedema after inguinal

lymph node dissection (ILND). Scientific evidence of their efficacy in preventing lymphoedema is

lacking. The primary objective of this study was to assess the efficacy of class II compression stockings

for the prevention of lymphoedema in cancer patients following ILND. Secondary objectives were to

investigate the influence of stockings on the occurrence of wound complications and genital oedema,

health related quality of life (HRQoL) and body image.

MethodsEighty patients (45 with melanoma, 35 with urogenital tumors) who underwent ILND

at two specialized cancer centers were randomly allocated to class II compression

stocking use for six months or to a usual care control group. Lymphoedema in the leg

and genital area, wound complications, HRQoL and body image were assessed at regular intervals

prior to and up to 12 months after ILND.

ResultsNo significant differences were observed between groups in the incidence of oedema, median time

to the occurrence of oedema, incidence of genital oedema, frequency of complications, HRQoL or

body image.

ConclusionBased on the results of the current study routine prescription of class II graduated compression

stockings after ILND should be questioned and alternative prevention strategies should be considered.

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IntroductionInguinal lymph node dissection (ILND) is performed in patients with lymph node metastasis of

melanoma, urogenital or anal tumours. ILND is associated with the frequent occurrence of short- and

long-term postoperative complications 1-3. The most notable long-term complication is lymphoedema

of the leg. The incidence of lymphoedema varies from 13 to 55% after ILND for melanoma 1,4,15 to

57 percent after ILND for penile cancer 5 and up to 69% after ILND in vulva cancer patients 4,6-8.

Risk factors include adjuvant radiotherapy, sartorius muscle transposition, and removal of the great

saphenous vein 7,9. Lymphoedema can have a negative impact on physical appearance, body- and

self-image, mobility, health-related quality of life (HRQoL) and finances 10,11.

There is currently no international consensus regarding preventive measures, resulting in consid-

erable variability in postoperative care. A graduated compression stocking has been advocated to

prevent oedema after inguinal node dissection 12. The efficacy of these stockings in obtaining and

maintaining volume reduction for manifest lymphoedema in the arm after axillary dissection has been

demonstrated 13-15. The efficacy of graduated compression stockings in preventing lymphedema after

removal of the (inguinal) lymph nodes has not yet been evaluated in a prospective, randomized trial.

Use of a stocking in the early postoperative period may influence the occurrence of early complica-

tions in either a positive or a negative way. The compression by the stocking may prevent seroma

accumulation in the groin but, alternatively, better drainage from the leg towards the groin may

stimulate seroma formation. Negative effects may include inflammation of the wound because of

friction, and lymphoedema of the genital area. Stocking use can also have both positive and negative

effects on Health Related Quality of Life (HRQoL). If stocking use reduces the risk of lymphoedema, it

may improve physical and psychosocial functioning. Yet, wearing a stocking may impact negatively on

body image and social participation.

The primary objective of this randomized controlled trial was to determine whether six months of

postoperative use of a class-II (23-32 mmHg) graduated compression stocking reduces the incidence

and severity of lymphoedema of the leg after inguinal lymph node dissection. Secondary objectives

were to investigate the impact of stocking use on the incidence of post-operative complications,

HRQoL and body image.

MethodsPatients and clinical setting

The study sample was composed of patients from two specialized cancer treatment centres in the

Netherlands, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital in Amsterdam and

the Erasmus MC-Daniel den Hoed Cancer Center in Rotterdam, who fulfilled the following inclusion

criteria: age >18 years, a diagnosis of melanoma, carcinoma of the penis or vulva and scheduled to

undergo ILND with curative intent for proven metastasis or as a prophylactic procedure. Exclusion

criteria were: pre-existing lymphoedema or prior episode of lymphoedema, prior or simultaneous

treatment with isolated limb perfusion, a history of deep venous thrombosis of the leg, local skin

disease, lack of basic proficiency in the Dutch language, and serious cognitive or psychiatric problems.

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Study design

In this multicentre randomized controlled trial, a minimization procedure 16,17 was used to dynamically

allocate participants to one of two groups: patient education alone or patient education combined

with the use of a class-II graduated compression stocking (23-32mmHg) for six months postopera-

tively. The minimization algorithm was designed to balance the groups on primary tumour (melanoma

or urogenital), additional deep node dissection (yes/no) and indication for adjuvant radiotherapy

(yes/no). The allocation procedure was concealed and performed by the clinical trials office of The

Netherlands Cancer Institute.

Lymph node dissection

Various types of incisions were used for the operation. An inguinal dissection was always performed,

removing the lymph nodes in the area that is confined by the medial surface of the long adductor

muscle, the sartorius muscle, an imaginary line just above the inguinal ligament and the adductor

canal. The base of the dissection is formed by the femoral vein and artery. The great saphenous vein

was preserved if this was deemed oncologically safe. Prophylactic antibiotics were given according to

local protocols. An additional deep dissection was not always performed, but when done included at

least the external iliac nodes. It could also encompass common iliac and obturator nodes. Vacuum-

drains were placed in the dissected areas. There was no strict protocol for prescription of antibiotics

or removal of the drains.

Postoperative care

On the first postoperative day, the patients in both groups were encouraged to sit in a chair with their

leg elevated, and they were fully ambulated from day two forward. All patients attended a single,

individual education session on minimizing lymphoedema risk. Additionally, all patients received

an information folder on prevention and treatment of lymphoedema. The intervention group was

prescribed a full-leg length class-II compression stocking, which was measured to fit before operation

and custom made, if necessary. The patients wore the stocking for at least one hour on the second day

after the operation. From this day forward, use of the stocking was increased gradually over a maximum

period of three days, until it was worn continuously during waking hours., If no lymphoedema was

present, stocking use was gradually reduced after six months. A physical therapist specialized in the

field managed all patients in whom lymphoedema developed during follow-up, following professional

guidelines. Seroma formation occurring after removal of the vacuum drains was managed with needle

aspiration.

Ethics

The institutional review boards of the participating hospitals approved the trial. All patients provided

written informed consent. The trial was registered with the Dutch trial register and the International

Standard Randomized Controlled Trial Number Register (ISRCTN23026635).

Primary outcome measure

The primary outcome was the first occurrence of lymphoedema in the ipsilateral leg. A specialized

physical therapist measured the volume of the leg, using the standardized Kühnke’s method of surface

measurement 18. This method involves circular measurements at 4 cm intervals that allow the calcu-

lation of the volume of the segment. Circumference methods have good reliability and applicability

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for trend measurement 19,20. The presence of pitting oedema was assessed through physical exami-

nation. Measurements were scheduled to coincide with regular (control) visits to the treating physician

preoperatively (T0), at the time of discharge from the hospital (T1), and at approximately two months

(T2), four months (T3), six months (T4) and 12 months (T5) postoperatively. Because the stocking leaves

visible marks when removed, the physical therapists performing the outcome assessments could

not be blinded, but they were blinded for their previous measurements. We defined lymphoedema

as a 10% or greater increase from baseline in volume of the proximal or distal half of the thigh or

the lower leg. We classified lymphoedema as nil (≤10% volume increase compared to the baseline

measurement), slight (10-20%), moderate (20-40%) or severe (>40%).

Secondary outcome measures

We abstracted the incidence of postoperative complications (infection, wound dehiscence and

seroma formation) within 30 days of the operation prospectively from the medical records. Infection

was defined as an inflammation for which oral or intravenous antibiotics were prescribed. Seroma

formation was defined as swelling that required needle aspiration that occurred after removal of the

wound drain. At each follow up visit, the physical therapist who performed the follow-up measure-

ments assessed the presence of (pitting) lymphoedema in the genital area by physical examination and

recorded lymphoedema requiring treatment and the reason for such treatment. Use of professional

homecare because of the stocking was also recorded. At T2, T3 and T4, we used a brief questionnaire

to query the user’s experiences and compliance (e.g. “Do you find the hose comfortable to wear?”

and “Are you able to put the stocking on without help?”).

We assessed HRQoL at T0, T4 and T5 using the Dutch version of the SF-36 Health Survey 21 and body

image at T4 and T5 using a cancer-specific body image scale 22. In the analysis, we focused on the two

SF-36 component scores, one for physical health and one for mental health 23.

Statistical analysis

A previously published observational study reported a 39% risk reduction for patients using stockings

compared to those who did not, with a 45.8% incidence in the control group 25. We performed statis-

tical power calculations on the assumption of a 40% incidence of lymphoedema in the control group.

With a total of 72 patients, the study would have 80% power to detect an absolute risk reduction

of 30% in the incidence of lymphoedema for the patients with a stocking compared to the control

group, with a two-sided p value of 0.05, using Fisher’s exact test 24. A risk reduction of 30% implies

that approximately three patients would have to wear a stocking to prevent one extra case of

lymphoedema, which we considered clinically acceptable. To account for possible loss to follow-up,

the sample size was set at 80 patients.

We generated descriptive statistics for relevant demographic and clinical characteristics at baseline.

For baseline comparisons, we used Fisher’s exact test for categorical variables and Student’s t-test or

Mann-Whitney U test for continuous variables. Similarly, we tested for between-group differences in

background characteristics resulting from loss to follow-up at each assessment point.

All analyses of primary and secondary outcomes were performed using an intention-to-treat approach.

For the incidence of lymphoedema at 6 and 12 months postoperatively, the incidence of wound

complications and genital oedema, and the need for lymphoedema treatment, we calculated relative

risks (RR) with 95% confidence intervals (95%CI) and corresponding p-values (Fisher’s exact test) based

on available observations. Additionally, to compare time-to-event between the two groups, we used

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a Cox proportional hazards model that adjusted for the stratification variables of the minimization

procedure 17 and relevant baseline imbalances. If lymphoedema occurred in both legs after bilateral

dissection, we used the earliest event in the analysis. The model incorporated all available data for all

patients. Patients who dropped out of the study before a first occurrence of lymphoedema were right

censored. We report the adjusted hazard ratio (HR) from the model with a 95%CI.

For all tests, we considered a two-sided p value ≤ 0.05 to be statistically significant. All statistical

analyses were performed using SPSS 18 for Windows (IBM SPSS, New York, USA).

Figure 1Consort diagram of the study

Randomized n = 80

Assessed for eligibility n =125

Allocated to stocking group n=41

Received intervention n=41

Allocated to no-stocking group n = 39

Received allocated intervention n=39

Analyzed n=37

Analyzed n=32

Lost to follow up/ censored n=7 •  Progressive disease (2) •  Refused due to study burden (1) •  Refused due to wound

complications (1) •  Discomfort (7) •  Died (3)

Lost to follow up/ censored n=4 •  Progressive disease (2) •  Refused due to study burden (2)

Discontinued intervention n=8 •  Discomfort (7) •  No Oedema (1)

Analyzed n=36

Analyzed n=32

Lost to follow up/ censored n=0

Lost to follow up/ censored n=1 (reason unknown)

enrollment

allocation

12 months

6 months

Excluded n=45

•  Did not meet inclusion criteria (21) •  Refused participation (24)

49

ResultsLymphoedema

Of 125 eligible patients, 80 (45 with melanoma and 35 with cancer of the urogenital tract) were entered

into the study. The median age was 59 years (range 20 - 85). Forty-one patients were allocated to

the intervention group and the other 39 to the usual care group. Figure 1 provides the reasons for

non-participation and displays the flow of participating patients through the study. The baseline

characteristics of the study sample are described in table 1. No significant differences between

groups in clinical characteristics were present at baseline or any follow-up point.

At 6 month follow-up (T4), 24 of 37 evaluable patients (65%) in the stocking group and

26 of 32 evaluable patients (81%) in the control group had developed lymphoedema (RR = 0.80,

95% CI 0.60 ; 1.07, p = 0.18). At 12 month follow-up (T5), 28 of 36 patients (77%) in the stocking

group and 27 of 32 patients (84%) in the control group had developed lymphoedema (RR = 0.92,

95% CI 0.73 ; 1.16, p = 0.55) (table 2). Sensitivity analysis with a last observation carried forward approach

yielded qualitatively similar results. RR’s for all time points are shown in figure 2. Lymphoedema was

classified as slight in all but 7 patients (4 in the stocking group and 3 in the control group, all of

whom had moderate lymphoedema). Cumulative incidence of lymphoedema was 80% for melanoma

patients and 57% for patients with cancer of the urogenital tract.

Genital oedema and early complications

There were no statistically significant group differences observed for genital oedema or wound

complications (table 2). Thirteen patients in the stocking group and 12 patients in the control group

developed more than a single wound complication. Genital oedema developed in 25 patients (31%)

and was resolved in 12 of these patients.

Multivariate time-to-event analysis.

Median time to diagnosis of lymphoedema was 18 weeks in the intervention group and 12 weeks

in the control group. After adjustment for preservation of the great saphenous vein, postoperative

radiotherapy and stratification variables, the hazard ratio was 0.69 (95%CI 0.38 to 1.26, p = 0.23) using

6 month follow-up data, and 0.70 (95% CI 0.40 to 1.24, p = 0.22) using 12 month follow-up data.

Patients’ experiences with the stocking

Data on experience with the stocking and compliance were available for 33 patients (80%). At T2, 25 of

these patients reported wearing the stocking daily. At four and six month follow-up, this was the case

for 24 patients. Six patients reported requiring assistance in putting on the stocking. At all assessment

points, approximately one-third of the patients reported that they deliberatly chose clothing that

covered up the stocking. Also, approximately one-third of the patients indicated that the stocking was

uncomfortable to wear. There were no significant differences in these ratings between patients who

had lymphoedema and those who did not, although patients with lymphoedema were more likely to

rate the stocking as comfortable than patients without lymphoedema.

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Table 1Baseline descriptives of the patients

Patients with stocking

Patients without stocking p-value

Number of patients 41 39

Gender

Male 20 23 0.38

Female 21 16

Median age in years (range) 59 (20 - 81) 58 (22 - 85) 0.65

Median body mass index (range) 27.7 (17.9 - 46.1) 24.5 (19.6 - 35.1) 0.46

Number of patients with a melanoma 22 23 1.00

Number of patients with a urogenital tumor 18 17

Number of Unilateral dissections 31 30 1.00

Number of Bilateral dissections 10 9

Inguino-femoral lymphnode dissection 41 39 1.00

Deep lymph node dissectiona:

External iliac 21 20 1.00

Common iliac 10 11 0.80

Obturator 16 14 0.82

Number of dissections with preservation of the great saphenous vein 10 14 0.34

Number of sartorius muscle transpositions 6 7 0.77

Prophylactic antibiotics

Yes 9 16 0.09

No 28 20

Unknown 4 3

Median number of removed lymph nodes (range) 13 (5 - 55) 12 (3 - 41) 0.88

Patients with initial bed rest 20 20 1.00

Median duration of bed rest in days (range) 2 (1 - 4) 1.5 (1 - 3) 0.98

Days with drainage Median (range) 10 (2- 28) 12 ( 1- 32) 0.54

Number of days until fully ambulated Median (range) 3 (1 - 7) 3 (1 - 7) 0.99

Postoperative day of discharge Median (range) 7 (1 - 18) 6 (3 - 24) 0.26

Number of patients with postoperative radiotherapy 4 7 0.34

Median duration of follow up in days (range) 336 (63 - 503) 327 (20 - 526) 0.74

aDeep dissection included at least the external iliac nodes

51

Table 2Univariate results of primary and secondary outcome measures.

Patients with

stocking

Patients without stocking

number numberRelative Risk

(95%CI) p-valueLymphoedema at 6 monthsa 24 26 0.80 (0.60 ; 1.07) 0.18

Lymphoedema at 12 monthsb 28 27 0.92 (0.73 ; 1.16) 0.55

Postoperative complications

Wound breakdown 9 7 1.25 (0.52 ; 3.03) 0.78

Infection 14 16 0.83 (0.47 ; 1.47) 0.65

Seroma formation 16 9 1.69 (0.85 ; 3.37) 0.15

Genital lymphoedema 11 14 0.75 (0.39 ; 1.44) 0.47

Patients requiring treatment for lymphoedema 21 22 0.91 (0.61 ; 1.36) 0.66

Reason for treatment:

Progressive oedema 8 11

Stiffness because of oedema 2 2

Sensation of heaviness of the leg 4 2

Abdominal/genital oedema 2 2

Other reasons 5 5

Patients requiring professional homecare 6 6

a N=37 for the stocking group and 32 for the control groupb N=36 for the stocking group and 32 for the control group

HRQoL and body image

Standardized mental and physical component scores for the SF-36 could not be calculated for 11

patients at T0 and three patients at T4, due to missing data. HRQoL and BIS data were not evaluable

for 21 patients atT4 and 33 patients at T5 due to loss to follow-up for these measures.

The available data indicated no significant differences between the groups at any assessment point

(Table 3).

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Table 3Quality of life and body image scores.

patients with

stocking

patients without stocking

Mean difference (95% CI) t- value Df 1 p-value

T0(baseline) n = 36 n = 33Mean SPCS2 (SD) 45.5 (12.2) 47.9 (9.2) 2.4 (-2.8 ; 7.7) 0.93 67 0.356Mean SMCS3 (SD) 48.7 (10.5) 51.5 (10.6) 2.8 (-2.3 ; 7.8) 1.1 67 0.275

T4(6 month follow up) n = 31 n = 25Mean SPCS (SD) 43.4 (11.1) 47.5 (9.4) 4.3 (-1.3 ; 9.9) 1.47 54 0.147Mean SMCS (SD) 51.2 ( 9.0) 53.7 (8.6) 2.4 (-2.2 ; 7.3) 1.29 54 0.202

BIS4 score n = 35 n = 25 Median (min ; max) 14 (10 ; 30) 14 (10 ; 27) 0.6625

T5(12 month follow up) n = 26 n = 21Mean SPCS (SD) 45.7 (11.7) 49.4 (9.0) 3.8 (-2.5; 10.0) 1.22 45 0.228Mean SMCS (SD) 51.7 ( 8.4) 52.9 (7.3) 1.3 (-3.4 ; 6.0) 1.25 45 0.218

BIS4 score n = 24 n = 23Median(min ; max) 15 (10 ; 34) 16 (10 ; 25) 0.8985

1Df = Degrees of freedom, 2SPCS = Standardized Physical Component Score of MOS-Short Form 36 Health Survey, 3SMCS =Standardized Mental Component Score of MOS-Short Form 36 Health Survey, 4BIS= BodyImage Scale, 5P-value as obtained from Mann-Whitney U test

DiscussionThere was no statistically significant difference in the incidence or severity of lymphoedema between

patients who used a class-II graduated compression stocking for a period of six months after ILND

and those who did not. The study was powered on the assumption of a 30% risk difference, while

the observed relative risk (if real) translates to a 14% risk difference in favour of the intervention

group. Considering the apparent absence of harmful effects of the stocking, some might judge this as

clinically relevant. At the same time, one needs to keep in mind that, based on these results, approx-

imately seven patients would need to use a stocking to prevent one extra case of lymphoedema.

Estimated time-to-event for lymphoedema was longer in the intervention group, but only by 6 weeks.

Our findings can be contrasted with those of Karakousis et al., who reported an absolute risk difference

of 39% between patients who wore stockings and those who did not 25. That study was observational

in nature, and thus it may have been biased by confounding. In a recent randomized controlled pilot

study of 22 patients with vulvar cancer, increase in leg volume was significantly less in the patients who

wore stockings than in those who did not 19. However, when using a clinically relevant cut-off of 10%

increase in leg volume, there was no statistically significant difference between the groups. This latter

finding is consistent with our results.

In the current study, there were some imbalances at baseline, although none of them were statisti-

cally significant. Median BMI was 3.2 points higher in the stocking-group. Although BMI is associated

with lymphoedema risk after axillary lymph node dissection, this is not the case for ILND 7,26-28.

53

Preservation of the great saphenous vein and postoperative radiotherapy were more common in the

control group. The latter imbalance occurred due to the fact that some patients who were not initially

scheduled to undergo radiotherapy actually did so, based on the postoperative pathology report.

Since these variables have been associated with increased risk of lymphoedema 4,26-28, we performed

a Cox-regression analysis that adjusted for these imbalances.

Wound complications occurred frequently in our study, but were not associated significantly with

stocking use. This is consistent with the results reported by Sawan et al.19.

It has been suggested that manual lymph drainage with or without the concomitant use of compression

garments has the potential to reduce lymphoedema risk. Studies in patients at risk for lymphoedema

after surgical treatment for breast cancer show inconsistent results with regard to the effectiveness of

this treatment, and no studies have been done in patients after ILND 29-31. Further research into this

subject is therefore necessary.

Because of the intensive follow-up regimen in the current study, all patients who developed swelling

of the leg could be diagnosed and treated in a timely manner. Preoperative volume assessment and

regularly scheduled follow-up visits, combined with patient education emphasizing the importance

of early detection may be more patient-friendly and (cost-)effective than preventive compression

therapy. This approach too, should be evaluated formally.

Some limitations of this study should be noted. First, it was not possible to blind either patient or

outcome assessors, which may have introduced some bias. We would note, however, that the Kühnke

volumetry method 18 used in our study consists of 18 to 22 circumference measurements per leg. The

physical therapists were blinded to their previous assessments at the time of taking measurements,

and it is improbable that they could have recalled their findings from several months earlier. Second,

the number of patients for whom follow-up ended because of a clinical event other than lymphoedema

was higher than anticipated, resulting in a somewhat larger chance of a type-II error. Relative risks

however, were stable throughout the study. Although more patients were lost to follow-up in the

control group than in the intervention group, it is unlikely that this biased the results, since the reasons

for dropout were not related to the outcome and there were no significant differences in frequency of

known risk factors between the groups at any time point.

Notable strengths of the study were the prospective assessment of lymphoedema and surgical

complications, and its randomized controlled design.

ConclusionSixty-nine percent of patients with melanoma or urogenital cancer experienced lymphoedema after

undergoing inguinal node dissection. The use of a graduated compression stocking did not reduce

the incidence of lymphoedema by the a priori criterion of 30%, nor was there a significant salutary

effect observed on the incidence of surgical complications, HRQoL or body image. Based on the

results of the current study, routine prescription of class-II graduated compression stockings after

ILND should be questioned and alternative prevention strategies should be considered.

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Figure 2Relative Risks for lymphoedema (grey dots) with corresponding 95%CI (whiskers), and threshold for a priori defined clinical relevance of the RR (dashed line) based on background risk at each timepoint. N, I0 and I1 indicate number of patients, cumulative incidence for lymphoedema for the stocking group (I1) and the no-stocking group (I0) up to that timepoint.

2 4a 6 12

0.0

0.5

1.0

1.5

2.0

Rela

tive

Risk

follow up (months)

n=74

I0=0.46

I1=0.41

n=70

I0=0.56

I1=0.47

n=69

I0=0.65

I1=0.81

n=68

I0=0.84

I1=0.78

a Missing data on lymphoedema were imputed using a ‘last value carried forward’ algorithm, only if the previous

and subsequent assessments were available and were the same. In all other cases, missing data were not

replaced. In total, 4 missing values were imputed (3 in the intervention group and 1 in the control group).

AcknowledgmentThe authors thank the surgical and nursing staff of the The Netherlands Cancer Institute and Erasmus

Medical Center-Daniel den Hoed for their help with patient recruitment and logistics, M. Sinneger,

P. van Dijen and H. Boogmans for their help with the measurements, and H. van Tinteren and P.M.

Bossuyt for their statistical and methodological advice.

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associated costs following inguinal lymph node dissection (ILND) in melanoma patients. Ann Surg Oncol 2010;17:2764-72.

2. Serpell, JW, PW Carne, M Bailey. Radical lymph node dissection for melanoma. ANZ J Surg 2003;73:294-99.

3. Nelson, BA, MS Cookson, JA Smith Jr., et al. Complications of inguinal and pelvic lymphad-enectomy for squamous cell carcinoma of the penis: a contemporary series. J Urol 2004;172494-97.

4. Abbas, S, M Seitz. Systematic review and meta-analysis of the used surgical techniques to reduce leg lymphoedema following radical inguinal nodes dissection. Surg Oncol 2011;20:88-96.

5. Spiess, PE, MS Hernandez, CA Pettaway. Contemporary inguinal lymph node dissection: minimizing complications. World J Urol 2009;27:205-12.

6. Gould, N. Predictors of Complications after Inguinal Lymphadenectomy. GynecolOncol 2001;82:329-32.

7. Rouzier, R, B Haddad, G Dubernard, et al. Inguinofemoral dissection for carcinoma of the vulva: effect of modifications of extent and technique on morbidity and survival. J Am Coll Surg 2003;196:442-50.

8. Carlson, JW, J Kauderer, JL Walker, et al. A randomized phase III trial of VH fibrin sealant to reduce lymphoedema after inguinal lymph node dissection: a Gynecologic Oncology Group study. Gynecol Oncol 2008;110:76-82.

9. Cormier, JN, RL Askew, KS Mungovan, et al. Lymphoedema beyond breast cancer: a systematic review and meta-analysis of cancer-related secondary lymphoedema. Cancer 2010;116:5138-49.

10. Ryan, M, MC Stainton, C Jaconelli, et al. The experience of lower limb lymphoedema for women after treatment for gynecologic cancer. Oncol Nurs Forum 2003;30:417-23.

11. Cheville, AL, M Almoza, JN Courmier, et al. A prospective cohort study defining utilities using time trade-offs and the Euroqol-5D to assess the impact of cancer-related lymphoedema. Cancer 2010;116:3722-31.

12. Karakousis, CP. Surgical procedures and lymphoedema of the upper and lower extremity. J Surg Oncol 2006;93:87-91.

13. Andersen, L, I Hojris, M Erlandsen, et al. Treatment of breast-cancer-related lymphoedema with or without manual lymphatic drainage--a randomized study. Acta Oncol 2000;39:399-405.

14. Vignes, S, R Porcher, M Arrault, et al. Long-Term Management of Breast Cancer-Related Lymphoedema after Intensive Decongestive Physical therapy. Breast Cancer Res Treat 2006;101: 285-90.

15. Stout Gergich, NL, LA Pfalzer, C McGarvey, et al. Preoperative assessment enables the early diagnosis and successful treatment of lymphoedema. Cancer 2008;112: 2809-19.

16. Altman, DG, JM Bland. Treatment allocation by minimisation. BMJ 2005;330:843.

17. Scott, NW, GC McPherson, CR Ramsay, et al. The method of minimization for allocation to clinical trials. a review. Control Clin Trials 2002;23:662-74.

18. Kühnke, E. Volumbestimmung aus Umlangmessungen. Folia Angiologica 1976:228-32.

19. Sawan, S, R Mugnai, Lopes Ade B, et al. Lower-limb lymphoedema and vulval cancer: feasibility of prophylactic compression garments and validation of leg volume measurement. Int J Gynecol Cancer 2009;19:1649-54.

20. Deltombe, T, J Jamart, S Recloux, et al. Reliability and limits of agreement of circumferential, water displacement, and optoelectronic volumetry in the measurement of upper limb lymphoedema. Lymphology 2007;40:26-34.

21. Ware, JE, Jr., CD Sherbourne. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30:473-83.

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23. Ware, JE, Jr., M Kosinski, MS Bayliss, et al. Comparison of methods for the scoring and statistical analysis of SF-36 health profile and summary measures: summary of results from the Medical Outcomes Study. Med Care 1995; 33:AS264-AS279.

24. Fleiss JL. In: Statistical methods for rates and proportions. John Wiley & Sons Inc.: New York, 1981; 24-26.

25. Karakousis, CP, MA Heiser, RH Moore. Lymphoedema after groin dissection. Am J Surg 1983;145: 205-08.

26. Spillane, AJ, RP Saw, M Tucker, et al. Defining lower limb lymphoedema after inguinal or ilio-in-guinal dissection in patients with melanoma using classification and regression tree analysis. Ann Surg 2008;248:286-93.

27. Ohba, Y, Y Todo, N Kobayashi, et al. Risk factors for lower-limb lymphoedema after surgery for cervical cancer. Int J Clin Oncol 2011;6:238-43.

28. Todo, Y, R Yamamoto, S Minobe, et al. Risk factors for postoperative lower-extremit lymphoedema in endometrial cancer survivors who had treatment including lymphadenectomy. Gynecol Oncol 2010;119:60-64.

29. Zimmermann, A, M. Wozniewski, A. Szklarska, et al. Efficacy of manual lymphatic drainage in preventing secondary lymphedema after breast cancer surgery. Lymphology 2012;45:103-112

30. Torres Lacomba M, Yuste Sánchez MJ, Zapico Goñi A, et al. Effectiveness of early physiotherapy to prevent lymphoedema after surgery for breast cancer: randomised, single blinded, clinical trial. BMJ. 2010 Jan 12;340:b5396. doi: 10.1136/bmj.b5396.

31. De Voogdt N, Christiaens MR, Geraerts I. Effect of manual lymph drainage in addition to guide-lines and exercise therapy on arm lymphoedema related to breast cancer: randomised controlled trial. BMJ. 2011 Sep 1;343:d5326. doi: 10.1136/bmj.d5326.

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CHAPTER 5Conservative interventions for preventing clinically detectable upper-limb lymphoedema in patients who are at risk of developing lymphoedema after breast cancer therapy

Martijn M Stuiver1,2, Marieke R ten Tusscher1, Carla S Agasi-Idenburg1, Cees Lucas2, Neil K Aaronson3*,

Patrick MM Bossuyt4*

1. Department of Physiotherapy, The Netherlands Cancer Institute - Antoni van Leeuwenhoek

Hospital, Amsterdam, Netherlands

2. Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical

Centre, University of Amsterdam, Amsterdam, Netherlands

3. Department of Psychosocial Research, Division of Psychosocial Research & Epidemiology, The

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands

4. Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of

Amsterdam, Amsterdam, Netherlands

5. *NKA and PMMB contributed equally to the manuscript

This chapter is based on a Cochrane Systematic Review (submitted).

The full protocol has been published in the Cochrane Database of Systematic Reviews 2012, Issue 4.

Art. No.: CD009765. DOI: 10.1002/14651858.CD009765.

60

ABSTRACT BackgroundBreast cancer related lymphoedema is one of the most bothersome long term sequelae of breast

cancer treatment. A number of studies have investigated the effectiveness of different treatment

strategies to reduce the risk of breast cancer related lymphoedema.

Objectives To provide an overview of current evidence on the effectiveness of conservative (non-surgical and

non-farmacological) interventions for prevention of clinically detectable upper limb lymphoedema

after breast cancer treatment.

Search methods We searched the Cochrane Breast Cancer Group’s (CBCG) Specialised Register, CENTRAL, MEDLINE

via PubMed, EMBASE via Ovid, CINAHL, PEDRO, PsychINFO, and the WHO International Clinical

Trials Registry Platform. We reviewed the reference lists of included trials and of relevant other reviews

that were identified in the search.

Eligible were all randomised controlled trials that used lymphoedema as the primary outcome, and

that compared any conservative intervention to either no intervention or to another conservative inter-

vention, in patients of both sexes and all ages at risk of developing lymphoedema in the upper limb

after treatment for breast cancer. We excluded studies that were non-randomised, studies that had

included patients who had been diagnosed with lymphoedema or cancer recurrence, or studies that

had not used a pre-defined, objective measure to assess lymphoedema. All studies identified through

the electronic searching were screened for eligibility by two authors (MS and MT) independently.

Data collection and analysis Three review authors independently extracted data on study characteristics, risk of bias, and outcomes

after interventions from reports of the included studies. Outcome measures included lymphoedema,

infection, range of motion of the shoulder, pain, psychosocial morbidity, level of functioning in activ-

ities of daily life (ADL), and health-related quality of life (HRQoL). Where possible, meta-analyses were

performed to generate summary estimates of effectiveness, in the form of relative risks or hazard

ratios for lymphoedema incidence and other dichotomous outcomes, and mean differences for range

of motion and patient reported outcomes on a continuous scale.

Results We were able to include ten trials. Overall, the quality of the evidence generated by these trials these

trials was low, due to risk of bias and inconsistency in the results.

61

manual lymph drainage

Four studies (385 patients) studied the effectiveness of manual lymph drainage (MLD). In two of these

studies MLD was added to education and/or exercises. The addition of MLD to standard physio-

therapy resulted in lower lymphoedema incidence compared to standard physiotherapy in only one

of these studies. Two other studies compared MLD combined with compression and exercise respec-

tively to education only. Both studies found lower incidence of lymphoedema in patients receiving the

combined intervention compared to patients who received education only.

Manual lymph drainage combined with either exercise or compression resulted in better shoulder

mobility for abduction and forward flexion in the first weeks after breast cancer surgery, compared to

education only (abduction 21.8 degrees; 95% CI: 13.6 to 30.1; forward flexion 14.4 degrees; 95% CI:

7.1 to 21.8). At medium term follow up the mean difference in improvement was 3.10 degrees (95%

CI: - 4.45 to 10.65) for abduction, and 0.40 degrees (95% CI: -8.25 to 9.05) for forward flexion, in

patients receiving education only compared to patients receiving MLD and compression. The mean

difference in abduction was 16.90 degrees (95% CI: 10.12 - 23.68) and in flexion 14.30 degrees (95%

CI: 7.11 - 21.49) in patiens receiving MLD and exercise compared to patients receiving exercise and

education only.

Two of the studies on MLD reported on pain, with inconsistent results. Results on HRQOL in two

studies on MLD were also contradictory. One study reported on functioning in activities of daily life.

Infection, and psychosocial morbidity had not been evaluated in any of the studies on MLD.

comprehensive outpatient follow-up

One study investigated the effects of a comprehensive outpatient follow-up program, consisting

of patient education, exercise, monitoring of lymphoedema symptoms and early intervention for

lymphoedema, compared to education only. Lymphoedema incidence at 24 months was lower in the

intervention group (RR: 0.34; 95% CI: 0.10 to 1.15). Patients in the intervention group had significantly

faster recovery of shoulder abduction.

early versus delayed start of shoulder mobilising exercises

Three studies (378 patients) had compared early versus delayed (>7 days postoperative) start

of shoulder mobilising exercises. The relative risk of lymphoedema after a delayed start was 0.59

(95% CI: 0.33 to 1.06). Shoulder mobility for forward flexion was better at one month and six months

follow-up after early exercise, compared to delayed exercise (two studies), but no meta-analysis could

be performed due to statistical heterogeneity. At 12 months follow-up (one study), there was no

difference in forward flexion between early and late start of exercise. One of the studies had evaluated

infection; the rates were 11% for an early start and 13% for a delayed start of exercise. One study

had evaluated ADL functioning: the mean difference at one year follow-up was 0.2 on the shoulder

disability questionnaire. One other study looked at pain: median scores were comparable at any point

up to two years follow-up. The study that had evaluated HRQoL reported a difference at one year

follow-up of 1.6 (95% CI: -2.14 to 5.34) on the Trial Outcome Index of the FACT-B. Two studies reported

on wound drainage volumes, one of which found higher volume in the early exercise group.

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resistance training

Two studies (351 patients) reported that resistance training does not increase the risk of developing

lymphoedema, provided that symptoms are monitored and treated immediately if they occur (RR

0.58; 95% CI: 0.30 to 1.13). One of these studies reported on pain and found that in the exercise group

patients reported pain more often at 3 months and 6 months. One of the studies reported on HRQoL:

the difference in %change at 12 months follow-up was 0.2 for the mental component score and 2.5 for

the physical component score. One study reported a risk of musculoskeletal injury in the resistance

training group of 3.4 per 100, compared to 0 in the control group. None of the other outcome measures of interest were reported in these trials.

Authors’ conclusions Because of the heterogeneity, the limited precision due to a low number of study participants, and the

risk of bias, the results of this review should be interpreted with caution. Based on the current available

evidence, we cannot draw firm conclusions about the effectiveness of physiotherapy interventions

containing MLD.

The current evidence does not indicate a higher risk of lymphoedema after early postoperative start of

exercises compared to a >7 days delay. Shoulder mobility is better at short-term follow-up after early

start of exercises, but wound drainage volumes may be increased. Progressive resistance exercise

therapy does not increase lymphoedema risk, provided that symptoms are closely monitored and

adequately treated if they occur.

High quality trials are needed to further evaluate all the interventions studied in this review.

63

BackgroundBreast cancer is the most common type of cancer among women. Worldwide, it has been estimated

that 1.38 million new cases were diagnosed in 2008. The incidence is especially high in the developed

countries of the world, with an estimated age standardised incidence in 2008 of 76 cases per 100,000

women in the United States, 83.2 per 100,000 in Canada, 84.8 per 100,000 in Australia and 89.7 per

100,000 women in Western Europe 1. Advances in breast cancer treatment have resulted in better

survival after diagnosis. As a consequence, an increasing number of people are confronted with early

and late side effects of breast cancer treatment.

One of the most important side-effects of breast cancer treatment is secondary lymphoedema. The

reported incidence of lymphoedema following breast cancer treatment varies from 6% to 54% 2-8

A recent systematic review and meta-analysis estimated the risk of developing arm lymphoedema

to be 16.6%, taking all studies into account, and 21% based on meta-analysis of cohort studies 9.

Lymphoedema incidence increases with the time since treatment 7,9,10. The variability in reported

incidence is due, in part, to differences in the criteria used to define lymphoedema 7,10.

Lymphoedema can be a debilitating condition that negatively affects health-related quality of life,

body image, finances, social participation and activity level 6,11,12 The economic burden of breast cancer

related lymphoedema was studied in a two-year follow-up study after breast cancer treatment in which

insurance claims data were used. The estimated difference in the two-year costs between women who

were diagnosed with breast cancer related to lymphoedema and those without lymphoedema ranged

from USD 14,877 to USD 23,167. The true costs may have been underestimated in that study because

of the use of claims data and the limited duration of follow-up 8.

Pathophysiology of lymphoedema

Lymphoedema is the accumulation of interstitial fluid as a result of insufficient lymph drainage 13. After

breast cancer treatment, secondary lymphoedema may occur as a result of insufficient lymph drainage

from the upper limb. This is due to partial or total destruction of the lymphatic system with surgery

or radiotherapy. Additionally, cancer treatment may induce qualitative changes in the structure of

the skin and subcutaneous tissues of the arm or trunk, such as scarring or subcutaneous fibrosis.

Insufficient lymph drainage due to these changes can also lead to the development of lymphoedema.

Diagnosis of lymphoedema

A variety of diagnostic criteria for the presence of lymphoedema are used. Lymphoedema may be

defined as a certain amount of absolute or relative change in limb circumference. Circumference can

be measured using a tape measure or perometry. Other criteria are absolute or relative changes in

total limb volume. Volume can be estimated from circumference measurements, water displacement

or laser scanning. Bioimpedance spectrometry can be used to estimate the amount of extracellular

fluid. The diagnosis of lymphoedema is sometimes made by self-reporting of symptoms. The wide

variety of ways to define and diagnose lymphoedema complicates the interpretation of research on

its incidence, prevalence, risk factors, treatment and prevention 6.

Risk factors

Findings in the literature on treatment-related and patient-related risk factors are inconsistent.

The treatment factor most consistently associated with lymphoedema is the extent of surgery.

Besides the extent of local surgery, this specifically includes axillary lymph node dissection and the

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number of lymph nodes removed 4,5,9,14-18. Radiotherapy has been associated with an elevated risk of

lymphoedema in some studies 3,19,20 but not in others 4,6,15,18,21,22. This inconsistency may be due, in part,

to the heterogeneity of radiotherapy treatment protocols. Of the clinical characteristics associated

with an increased risk of developing lymphoedema, higher body mass index (BMI) and higher body

weight are the most consistent 4,5,9,15,16,21,22. Other clinical risk factors include positive lymph nodes and

advanced disease 3,5,15,17,18. Coming from a black race has also been suggested as a risk factor in some

studies 3,4, although other studies found no such association 6,15,18. Higher age has been identified both

as a risk factor 14 and as a protective factor 3,4,15. Higher education or socioeconomic status has also

been identified both as a risk factor 4 and as a protective factor 3,14.

Interventions

Various preventive interventions are employed to minimise the risk of developing lymphoedema after

treatment for breast cancer. For this review, we considered conservative interventions: non-surgical

and non-farmacological interventions. These include, but may not be limited to, the interventions as

described below.

Exercise

Performing exercise has been debated to be both a risk factor and a risk-reducing factor 23. Exercise

increases blood flow and the blood pressure in the upper limb, and consequently increases lymph

production. On the other hand, muscle activity in the limb stimulates lymph flow (often referred to

as the ‘muscle pump’), improving lymph drainage. Interindividual physiological variation seems to

exist with regards to changes in lymphatic drainage during exercise 24. Exercises that specifically aim

to stimulate lymph flow from the extremity towards the thorax may, if effective, lower the risk of

developing lymphoedema. Exercises that improve the range of motion and strength of the upper

limb may also improve daily use of the arm thus improving lymph drainage though muscle activity 25.

Patient education

Patient education can be provided verbally, or through written materials. Education is intended to

help patients understand the changes in fluid regulation in the affected limb and the influence of

external factors on fluid regulation. Risk minimisation strategies may additionally be discussed as

part of the education, including lifestyle advice, such as maintaining activity levels and a healthy

BMI, information on early self-detection of lymphoedema, and measures that can be taken in case of

swelling 5,25. Although education may be effective in encouraging preventive self-care measures, it

may also unintentionally reduce other forms of behaviour, such as activities involving the arm on the

affected side 26.

Monitoring and early intervention

Monitoring involves regular follow-up appointments to objectively judge the status of the affected limb

and to reinforce behaviour that is thought to be beneficial for preventing lymphoedema. Subclinical

lymphoedema may be diagnosed with the help of techniques such as bioimpedance spectrometry

or whole limb perometry. The rationale for monitoring is that the sooner lymphoedema is diagnosed

then the sooner it can be adequately addressed, thus limiting morbidity 27.

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Compression therapy

Compression therapy may consist of wearing compression garments in various compression classes,

and using bindings or pneumatic compression devices. The rationale for compression therapy is based

on providing resistance to swelling, as well as improving the ‘muscle pump’ function. Compression

therapy has been recommended for the treatment and control of manifest lymphoedema of the

limbs 28, but is also sometimes used for prevention of lymphoedema.

Manual lymph drainage

Manual lymph drainage (MLD) is a massage technique that involves gentle compression of the skin to

stimulate lymph flow and manual stimulation of lymph nodes to increase their activity. MLD generally

aims at improving the quality of the oedema and reducing or stabilising lymphoedema. Reducing

lymphoedema is achieved by stimulating the formation of physiological lymphatic shunts or alter-

native pathways for lymph drainage. Some evidence suggests that MLD could be effective in reducing

upper limb volume in patients with existing lymphoedema although it is usually combined with other

treatment modalities 28-30. Some advocate the use of MLD to prevent lymphoedema by activating

alternative drainage pathways 29. Techniques of manual lymphdrainage may also be used to improve

tissue consistency and tissue compliance of the surgical scar, with the objective to improve lymphatic

flow through the tissue and range of motion.

Lymph taping (Kinesiotape)

The concept of lymph taping is relatively novel. This therapy involves the application of elastic,

thermo-adhesive tape in such a way that lymph drainage towards the lymph nodes is facilitated.

Kinesiotape has been suggested as a replacement for bandaging in the treatment of lymphoedema 20.

Why it is important to do this review

Considering the impact of lymphoedema on the quality of life of patients after breast cancer therapy

and the associated societal costs, efforts should be made to prevent its occurrence. Unfortunately,

there is no conclusive evidence to date on the optimal strategy to prevent lymphoedema. Preventive

treatments carry with them direct and indirect costs that should be balanced against possible gains.

A research recommendation for a systematic review addressing this subject was made in the NHS

Database of Uncertainties about the Effects of Treatments 31. The review presented here aims to

summarize current evidence in such a way that it can be used to guide clinical decisions, and support

the development of evidence-based guidelines for the prevention of lymphoedema in patients with

breast cancer.

Objectives To estimate the effectiveness of conservative therapies for the prevention of lymphoedema in (specific

subgroups of) patients who are at risk of developing lymphoedema after treatment for breast cancer.

To compare the effectiveness of the different interventions.

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Methods Criteria for considering studies for this review

Types of studies

We considered all types of randomised controlled trials (RCTs) eligible for inclusion that had reported

secondary lymphoedema as the primary outcome, and had compared a conservative intervention to

either usual care, placebo intervention, or some other intervention.

Types of participants

We included trials in patients of both sexes and all ages at risk of developing lymphoedema in the

upper limb after treatment for breast cancer. Treatments for breast cancer could include: surgical

treatment for breast cancer with axillary lymph node dissection, sentinel lymph node biopsy or axillary

sampling, with or without radiotherapy to the axilla or the supraclavicular fossa or both; or radio-

therapy alone. Trials in patients who had been diagnosed with lymphoedema or cancer recurrence

were not eligible for inclusion.

Types of interventions

We considered trials of exercise therapy, patient education, monitoring and early intervention,

manual lymph drainage (MLD), compression therapy (bandages, a compression sleeve, pneumatic

compression) and lymph taping; or any combination of these interventions. We also considered

trials with other non-farmacological and non-surgical interventions eligible for inclusion if they were

identified in the search, provided that the studies met the other inclusion criteria.

Types of outcome measures

Primary outcomes

The primary outcome in our review is the occurrence of lymphoedema. This could be reported as

either a dichotomous outcome or as a continuous outcome (volume or percentage volume change).

Time-to-event data, with lymphoedema as the event, was also used, if reported. Because of the variety

of ways in which lymphoedema can be defined and diagnosed, studies were only considered eligible

if they had used a predefined criterion for establishing lymphoedema that that was based, at least in

part, on an objective assessment. This included circumference measurements, water displacement

methods, bioimpedance measurements, laser scanning, perometry and dual energy X-ray absorpti-

ometry (DEXA) scanning. This means we did not include studies that had evaluated an intervention

based solely on a diagnosis of lymphoedema made by a healthcare professional or on self-reported

swelling or complaints of oedema.

Secondary outcomes

Secondary outcome measures of interest were:

• infection, defined as any inflammation (redness, pain, heat and swelling) for which antibiotics are prescribed;

• active range of motion (AROM) of the upper limb;

• level of functioning in activities of daily living (ADL), as a self-reported measure or as rated by an assessor using a validated measurement instrument.

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The following self-reported measures were also included as secondary outcomes, whenever assessed

with a validated measurement instrument:

• pain;

• health-related quality of life (including both physical and mental well-being);

• psychosocial morbidity (emotional or psychosocial distress).

Any reported adverse effects of the preventive treatments were documented.

Search methods for identification of studies

No language or publication date restrictions were imposed. We only considered research that has

been published in peer-reviewed scientific journals.

Electronic searches

We searched the following databases.

(a) The Cochrane Breast Cancer Group’s (CBCG) Specialised Register. Details of the search strategies used by the Group for the identification of studies and the procedure used to code references are outlined in the Group’s module 32. Trials with the key words ‘lymphoedema’, ‘upper-limb lymphoedema’, ‘exercise’, ‘education’, ‘patient monitoring’, ‘manual lymph drainage’, ‘compression therapy’, compression bandages’, ‘compression sleeve’, ‘pneumatic compression’, ‘lymph taping’ and ‘kinesiotape’ were extracted and considered for inclusion in the review.

(b) MEDLINE via PubMed. See Appendix 1 for the search strategy.

(c) EMBASE via Ovid (1980 to May 2013). See Appendix 2 for the search strategy.

(d) The World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/Default.aspx) for all prospectively registered and ongoing trials. See Appendix 3 for the search strategy.

(e) The Cumulative Index to Nursing and Allied Health Literature (CINAHL) through EBSCO (1980 to May 2013). See Appendix 4 for the search strategy.

(f) The Physiotherapy Evidence Database (PEDro) via http://www.pedro.org.au/ (1980 to May 2013). See Appendix 5 for the search strategy.

(g) PsycINFO through Ovid (1980 to May 2013). See Appendix 6 for the search strategy.

(h) The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, April 2013). See Appendix 7.

Searching other resources

References of included articles and relevant identified reviews were handsearched for previously

unidentified studies.

Data collection and analysis

Selection of studies

All the studies identified through the electronic searching were screened for eligibility by two authors

independently (MS and MT or CA). An initial selection was carried out based on the title of the study.

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Articles were classified as potentially eligible if the title indicated a randomised controlled trial (RCT)

on the prevention of lymphoedema using a conservative therapy. If no judgment could be made

about the eligibility of a study based on the title, the judgment was based on title and abstract.

Any disagreements about eligibility were resolved in consensus meetings. The same procedure was

applied to references found in included studies. Review articles identified in the search were screened

for relevance and reference lists were checked to identify additional potentially eligible studies. Final

decisions about inclusion for all articles judged potentially eligible were based on the full text of the

study report.

Data extraction and management

Two authors (MS and MT) performed data extraction independently, using data collection forms that

were developed and pretested for the purpose of this study. In the case of disagreement, agreement

was reached in a consensus meeting. If no consensus could be reached, the decision was made by a

third author (CA).

For each included study, the following characteristics were collected:

1. study information (year, country, setting, sample size, method of randomi-sation, blinding and method of outcome assessment including the definition of lymphoedema in the case of a dichotomous outcome, duration of follow-up);

2. baseline characteristics of study participants (age, disease stage);

3. intervention used for the prevention of lymphoedema (type of treatment, dosage of treatment, description of usual care condition);

4. comparator (alternative intervention or follow-up only);

5. aggregated outcomes (event rates for dichotomous data or means and standard deviations for continuous data);

6. adverse effects reported; and

7. loss to follow-up (number and reasons).

If the data and methods reported were insufficient for data extraction or risk of bias assessment,

the authors of included studies were contacted for additional information.

Assessment of risk of bias in included studies

Risk of bias was assessed using the Cochrane risk of bias tool for the appraisal of RCTs, as outlined

in the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 33. The tool contains

six domains and each domain was assigned a judgement related to the risk of bias. The judgement

could be ‘low risk’, ‘high risk’, or ‘unclear risk’. The latter judgement was assigned if the risk of bias of

a characteristic in an included study was judged to be unclear, or if there was insufficient information

on which to base the judgement.

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The six domains are:

1. sequence generation;

2. allocation concealment;

3. blinding of participants, personnel and outcome assessors;

4. incomplete outcome data;

5. selective outcome reporting; and

6. other sources of bias.

Other sources of bias specifically addressed were comparability of the groups at baseline, intention

to treat analysis, and equal treatment of groups except for the allocated intervention. Specifically,

additional contact with a healthcare professional due to the nature of the intervention may also

reinforce risk-reduction behaviour, such as self-care; this may result in overestimation of the effect.

Since the effectiveness of self-care and other risk reduction behaviour is unclear, risk of bias from

other sources was set to unclear if this was the only potential source of bias, or high if there were

additional concerns related to risk of bias from other sources. Judgements on comparability of groups

at baseline were based on magnitude of the differences rather than statistical significance.

Two authors (MS and MT) independently assessed each included trial for risk of bias. Results were

compared and discussed in a consensus meeting. If no consensus could be reached, a third author

(CA) made the decision. In cases where no clear judgement could be reached based on the trial

report, the trial authors were contacted to obtain additional details. The risk of bias is reported with

a risk of bias table and graph for each outcome measure.

Measures of treatment effect

Statistics to express treatment effects are reported for each outcome separately. We used the measure

of effect as estimated in the intention-to-treat analysis. The method of assessment is reported for

each outcome.

Dichotomous outcomes

For studies reporting event rates, we used the relative risk as a measure of effect.

For dichotomous outcomes, such as a diagnosis of lymphoedema, the treatment effect was expressed

as a risk ratio with 95% confidence intervals.

Continuous outcomes

For continuous outcomes, such as limb volume, and self-reported measures, such as health-related

quality of life, psychosocial morbidity, level of ADL functioning and active range of motion of the

upper limb, the treatment effect was expressed as the mean difference or the standardised mean

difference, if different scales had been used. If no mean differences and confidence intervals were

reported, they were calculated from the available summary data using Review Manager software

(The Nordic Cochrane Centre, The Cochrane Collaboration).

For outcome variables measured with the same instrument, final scores and change scores

(the difference between baseline scores and final scores) could be reported in the included trials.

If final scores and change scores could be pooled, they were presented for subgroups in the corre-

sponding forest plot. If it was not possible to extract standard deviations for a particular outcome,

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attempts were made to obtain the standard deviations from the study authors. If no further details

could be obtained, missing standard deviations were imputed using the square root of the average of

the variances (standard deviation squared) from all other included studies for that measure.

Time-to-event outcomes

For time-to-event outcomes, such as time to diagnosis of lymphoedema, the treatment effect was

expressed as a hazard ratio.

Dealing with missing data

For trials listed in trial registers, reported outcomes were compared with those specified in the

protocol. If outcomes as described in the methods section of the publication or the trial registration

file were not presented in the available publications, the authors were contacted for additional details.

Assessment of heterogeneity

Three authors (MS, MT and CA) jointly judged the extent of clinical heterogeneity for studies that had

comparable goals and type of intervention, but differences with respect to treatment protocols or

population. Outcomes that were judged potentially eligible for meta-analyses were used to generate

summary measures of treatment effect. Subsequently, statistical heterogeneity was assessed by visual

inspection of the forest plots and quantified using the Chi2 statistic and the I2 statistic, as provided by

Review Manager software.

For the Chi2 statistic, a P value of 0.10 was set to indicate statistically significant heterogeneity, rather

than the conventional value of 0.05. The I2 statistic indicates the percentage of the variability in effect

estimates that is due to heterogeneity. We considered an I2 statistic greater than 50% as large. The

value of the I2 statistic was evaluated alongside the magnitude and direction of effect and the P value

for the Chi2 statistic for heterogeneity 33.

Data synthesis

Treatment effects from studies with comparable interventions and outcomes were visualized in forest

plots. Summary estimates were calculated only if statistical heterogeneity was within the pre-specified

limits of acceptability. The results were stratified according to the duration of follow-up, combining

studies with short follow-up (<six months) and medium length follow-up (6 months up to two years)

and long term follow-up (> 2 years) in separate plots.

For continuous outcomes, mean differences (MD) were used for limb volume and standardised mean

differences (SMD) for self-reported measures.

Fixed-effect (inverse-variance method) analyses were conducted on all occasions considering the

small number of studies 34. All analyses were performed using Review Manager software in accordance

with the Cochrane Handbook for Systematic Reviews of Interventions and R 3.0.1 35

Results A total of 2570 records were identified in the initial search, of which six were relevant reviews. In

the reference lists of these reviews, one additional potentially eligible study was identified. Figure 1

provides full information on study selection. After removing duplicates 1702 unique titles remained.

Of these, 1679 were excluded based on title and abstract.

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Figure 1

Flowchart of study selection

1702 records after duplicates removed

2570 records identified through database searching

1679 records excluded

10 studies included in review

13 articles exluded

•  Not a conservative intervention (2) •  Primary outcome not lymphoedema (5) •  Lymphoedema nog defined by objective measure (3) •  Not all participants at risk at baseline (1) •  Not a primary study (1) •  Not a randomized controlled trial (1) •  No full trial report available (1)

Meta analyses on primary outcome:

•  2 resistance exercise studies •  3 postoperative exercise studies

1 additional record identified through relevant systematic review

1702 records after duplicates removed

23 full-text articles assessed for eligibility

Meta analyses on scondary outcome (shoulder range of motion):

•  2 physiotherapy + MLD studies in 2 meta-analyses •  3 postoperative exercise studies in 1 meta-analysis •  2 postoperative exercise studies in 1 meta-analysis

Included studies

Twenty-three of the 1702 unique records were retrieved for full text evaluation. Of these ten fulfilled

all inclusion criteria 25,29,30,36-43. For three of the included studies additional publications were available.

These publications concerned reports on additional outcome measures 42,44,45, a publication on the

trial protocol46 , and a paper on adverse events 47.

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All included studies had evaluated the occurrence of lymphoedema, but different study questions and

interventions had been addressed.

• Four trials in five publications investigated the effectiveness of manual lymph drainage, alone or in combination with other interventions, for the prevention of lymphoedema after breast cancer surgery 29,30,37,42,43.

• Two studies in four publications were non-inferiority trials investigating the safety of progressive resistance exercise after breast cancer surgery, with regard to lymphoedema risk 39,40,45,47.

• Three studies investigated the influence of different postoperative rehabili-tation protocols: early versus late start of shoulder mobilization exercises after surgery for breast cancer, on the risk of subsequent secondary lymphoedema 36,38,41.

• One study investigated the effects of a comprehensive out-patient physio-therapy program for women surgically treated for breast cancer, that included education, monitoring, exercise and early intervention for prevention of lymphoedema 25.

Six studies included shoulder range of motion as a secondary outcome measure 29,36-38,41,42.

Four studies reported pain as a secondary outcome measure 29,36,37,39.

Four studies included HRQoL as a secondary outcome measure 30,37,41,45.

We did not identify any studies evaluating the effectiveness of lymph taping for prevention

of lymphoedema. Full details on trial characteristics and outcomes are provided in Table 1.

Excluded studies

Thirteen full-text publications were excluded. These publications and the reasons for exclusion are

listed in Table 2. Ongoing studies

Two ongoing studies were identified; see Table 3 for trial characteristics.

Risk of bias in included studies

Information on one or more items related to risk of bias was unclear or not-reported in seven

studies 25,29,30,36-38,43.The authors of these studies were contacted for further clarification, and the

missing information was obtained in all but one case 38.

All studies had used a randomization, but allocation concealment was not sufficiently ensured in three

studies 25,36,43. None of the studies relied on blinding of study participants, and outcome assessment of

measured outcomes was judged sufficiently blinded in only four studies 37,38,40,41. Although compliance

to the experimental intervention was measured and reported in some studies, this was not the case

for the compliance to the control condition in all but two studies 39,40. Risk of bias due to attrition or

selective reporting was low in most studies. Other sources of risk of bias were associated with patients

having more contact with a healthcare professional compared to the control group 37-39,43 and baseline

imbalances 37,38.

Detailed information on risk of bias for all studies is described in Table 1. Figure 2 summarizes risk of

bias per domain for all studies.

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Figure 2

Risk of bias (white: no risk of bias, grey: unclear risk of bias,

black: high risk of bias) in included studies.

Effects of interventionsManual lymph drainage (MLD)Incidence of treatment failure (occurrence of lymphoedema)

Four trials tested MLD alone or in combination with other interventions. In two of these studies,

manual lymph drainage as an added intervention to usual care was investigated, allowing for the

evaluation of the unique effect of MLD 30,43. Two other studies investigated the effect of MLD in

combination with another intervention, compared to education alone 29,37.

In one study, both cumulative incidence up to each follow-up point and point prevalence at each

follow-up point were reported 30. In three other studies no explicit distinction was made and reported

numbers were treated as cumulative incidence 29,37,43.

Due to substantial clinical and statistical heterogeneity both for short-term (<6 months) and

medium-term (>6months, <24months) follow-up, (I2 = 86%; P=0.008 and I2 = 84%; P < 0.001

respectively for RR and I2 = 84%, P=0.01 for the unadjusted HR), no meta-analyses were performed.

A narrative summary of the results is provided below.

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Castro 2011

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Schmitz 2010

Todd 2008

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Zimmmermann 2012

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Physiotherapy including MLD versus physiotherapy without MLDOne study that investigated MLD in addition to routine physiotherapy consisting of exercises of the

upper limb and chest, compared to a control group that had routine physiotherapy only, found a

large lymphoedema risk-reducing effect of MLD (RR=0.14, 95% CI: 0.04 - 0.58, at 3 month follow-up;

RR=0.02, 95% CI: 0.00 - 0.33, at 6 months follow-up) 43. Risk of bias in this study was high. Another

study, with moderate risk of bias, found no added value of MLD in combination with routine

physiotherapy consisting of exercises and education, in comparison to routine physiotherapy only

(RR=1.40, 95% CI: 0.51 - 3.86, at 3 month follow-up; RR=0.96, 95% CI: 0.45 - 2.05, at 6 month follow-up,

RR=1.26, 95% CI: 0.69 - 2.32, at 12 month follow-up) 30. In this study, comparisons were also made for

time-to-event for the occurrence of lymphoedema. There was no statistically significant difference

between the groups (unadjusted HR 1.3, 95% CI: 0.6-2.5). Results on lymphoedema risk as defined by

a different criterion (an increase of 2cm or more in the difference in arm circumference between the

affected and healthy side at two or more adjacent measurement points compared with the difference

before surgery), which was included as a secondary outcome measure, were qualitatively similar.

MLD in combination with other interventions versus education onlyOne study compared a combined intervention of MLD, compression, scar massage and education to

education alone. This study reported a reduction in lymphoedema risk, for the intervention group, but

the 95% confidence interval as calculated from the available data was wide and included 1 (RR=0.17,

95% CI: 0.02 - 1.28, reported P=0.042 at 8 month follow-up) 37. Risk of bias in this study was moderate.

A second study compared MLD combined with exercise therapy and education to education only 29. In

this study, there was a statistically significant reduction in lymphoedema risk at the 12 month follow-up

in favour of the intervention group (RR=0.28; 95% CI: 0.10-0.79). Time-to-event in this study was also

statistically significantly in favour of the intervention group (unadjusted HR 0.26; 95% CI: 0.09-0.79).

Risk of bias in this study was high.

Infection

No data on this outcome

Active range of motion (AROM) of the upper limb

Two studies examined the effect of early physiotherapy consisting MLD plus exercise on shoulder

range of motion 29,42. Both studies had high risk of bias.

Pooling the results of the early postoperative phase (≤ 3 weeks) resulted in a mean difference for

abduction of 21.8 degrees (95% CI: 13.6 to 30.10, Analysis 1.1), and a mean difference for forward

flexion of 14.4 degrees (95% CI: 7.1 to 21.8 degrees, Analysis 1.2). At medium term follow-up

(≥6 months ≤ 24), one of the studies reported a small and statistically non-significant difference in

improvement of shoulder range of motion from first postoperative day at the 12 month follow-up

of 3.10 degrees (95% CI: - 4.45 to 10.65) for abduction, and of 0.40 degrees (95% CI: -8.25 to 9.05)

for forward flexion, in favour of the control group 29. The other study reported a statistically signif-

icant mean difference of 16.90 degrees (95% CI: 10.12 - 23.68) for abduction and 14.30 degrees

(95% CI: 7.11 - 21.49) for forward flexion, in favour of the intervention group 42. No meta-analyses could

be performed due to considerable statistical heterogeneity (I2 = 93%, and I2 = 85%, for abduction and

forward flexion respectively). Only one of the studies included range of motion for rotations and found

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a small and statistically non-significant difference in recovery of medial rotation (15 versus 9.8 degrees

improvement; 95% CI for the difference in means: 3.6 to 10.77 ) and lateral rotation (7.6 versus 6.8

degrees improvement, 95% CI for the difference in means: 1.09 to 5.91) in favour of the early physical

therapy group at respectively three weeks and 12 months after the first postoperative day 29.

Analysis 1.1Short term range of motion for shoulder abduction, early physiotherapy including MLD vs no physiotherapy or physiotherapy without MLD

Analysis 1.2Short term range of motion for shoulder forward flexion, early physiotherapy including MLD vs no physiotherapy or physiotherapy without MLD

ADL function

No data on this outcome.

Pain

Two studies, both with high risk of bias, addressed pain as a secondary outcome and both evaluated

combined interventions including MLD versus education alone 29,37. In one study, patients who received

manual lymph drainage, exercise and education reported greater improvement in pain score from

baseline at three weeks (- 4.2 versus -3.8 on a 0-10 scale, 95% CI: -0.72 to 1.72 ) but less improvement

at 12 months (-4.5 versus -5.0, 95% CI: -1.62 to 0.62), compared to patients who received education

alone 29.

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In the other study, patients receiving MLD and using a compression sleeve for 8 months reported

lower pain scores on a 0-10 scale, compared to patients who received education only. The mean

difference between groups and the corresponding 95% CI: as calculated from the provided means

and 95%CIs per group was -2.37 points (95% CI: -4.52 to -0.22) 37.

Health-related quality of life (HRQoL)

MLD in combination with other interventions versus education onlyTwo studies on MLD assessed HRQoL as a secondary outcome measure 30,37. Due to clinical heteroge-

neity meta-analysis was deemed inappropriate and a narrative synthesis is provided here.

One of these studies found no statistically significant differences in the mental and physical summary

component scores of the 36-item Medical Outcomes Study Short-Form (SF-36) between patients who

received MLD in combination with exercise and education and patients who received exercise and

education only 30. This study had moderate risk of bias. In the other study, patients receiving MLD

plus compression had statistically significantly better scores than patients receiving education only,

for physical functioning (144 versus 109), social functioning (144 versus 124), fatigue (47 versus 71)

and financial difficulties (6 versus 14) as measured with the EORTC-QLQ-C30 questionnaire 37. Risk

of bias in this study was high. In particular, there were baseline differences in several domains of the

QLQ- C30 (see ‘other types of bias’ in for Castro-Sanchez 2011 in Table 1).

Psychosocial morbidity


Adverse events


ExerciseIncidence of treatment failure (occurrence of lymphoedema)

Early versus delayed onset of mobilising shoulder exercises after breast cancer treatmentThree trials, all with high risk of bias for the primary outcome, investigated the influence of early

versus delayed onset of full range mobilising shoulder exercises after breast cancer surgery 36,38,41.

Meta-analysis resulted in a summary estimate of the difference in risk of lymphoedema at medium-term

follow-up (6-12 months) between early or late start of full range exercises of 0.59 (95% CI: 0.33 to 1.06)

(Analysis 2).

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Analysis 2lymphoedema risk after early versus delayed start of postoperative shoulder exercises

Safety of progressive resistance exercise after breast cancer treatmentThe meta-analysis of two non-inferiority studies indicated that weight training after breast cancer

treatment did not increase lymphoedema risk (summary RR 0.58; 95% CI: 0.30 to 1.13; Analysis 3) 39,40. One of these studies compared a supervised physiotherapy program of moderate progressive

resistance exercises (starting at 0.5 kg) 2-3 times a week, with a regimen of activity restriction

(i.e. avoiding heavy or strenuous physical activities, including aerobic or other types of exercise classes

involving heavy upper limb physical activity, and lifting and carrying objects over 3 kg) and physio-

therapy (passive mobilization and massage) once a week for 6 months. In both groups, lymphoedema

treatment was started if patients reported symptoms 39. RRs calculated from reported point preva-

lences were 0.69 (95%CI, 0.23 to 2.09), 0.52 (95% CI: 0.16 to 1.67) and 1.04 (95% CI: 0.51 to 2.09)

at three months, six months and 24 months respectively. This study had high risk of bias.

The second study, with moderate risk of bias, compared progressive resistance exercise (starting

with the lowest weight, and using the smallest possible increments) plus immediate treatment of

lymphoedema at first symptoms versus no exercise, and accepted the equivalence hypothesis on

lymphoedema risk (RR=0.64; 95% CI: 0.28 to 1.45) 40.

Analysis 3lymphoedema risk of progressive resistance exercises

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Infection

Early versus delayed onset of mobilising shoulder exercises after breast cancer treatmentInfection rates were reported in one study 38. No statistically significant differences in wound infection

rates were observed between early supervised start of mobilising shoulder exercises compared to

a delayed start (RR: 0.83; 95% CI: 0.20 to 3.39). Risk of bias for this outcome was unclear.


Early versus delayed onset of mobilising shoulder exercises after breast cancer treatmentThree studies reported on early versus delayed full range shoulder mobilisation after breast cancer

surgery 36,38,41. Two of the studies reported on short-term results, and included a one month follow-up

measurement 36,38. Data-pooling was possible for shoulder internal rotations only, due to statistical

heterogeneity for forward flexion (I2 = 97%), abduction (I2=97%) and external rotation (I2=89%).

In both studies, patients with an early start of exercises had better forward flexion at one month;

7 degrees (95% CI: 3 to 11) 36 and 36 degrees (95% CI: 27 to 45) 38, respectively. Abduction did not

differ significantly at one month in one study 36. In the other study, the early exercise group had better

shoulder function at one month: mean difference for abduction 43 degrees, (95% CI: 32 to 55) 38.

External rotation did not differ significantly at one month in one study 36. In the other study, the early

exercise group had better function at one month (mean difference 15 degrees, 95% CI: 7 to 23) 38.

The pooled estimate for internal rotation at one month showed no statistically significant or potentially

clinically relevant difference as indicated by the 95% confidence interval, between early and delayed

shoulder exercises (Analysis 4.1).

All three studies reported medium-term follow-up, of which two reported a 6 month follow-up 36,38

and one a 12 months follow-up 41. Data-pooling was possible for shoulder internal rotations only, due

to statistical heterogeneity for forward flexion (I2=90%), abduction (I2=92%, ) and external rotation

(I2=58%). Forward flexion was statistically significantly better at 6 months for patients who started

early with full range shoulder exercises compared to patients who followed a delayed approach.

The difference was 5 degrees (95% CI: 2 to 8) 36 and 15 degrees (95% CI: 11 to 20) 38, respectively.

In the third study there was no difference in forward flexion at 12 months follow-up 41. One of the

studies also included a measurement at two years follow-up and found a difference of 3 degrees (95%

CI: 0 to 6), once again in favour of the early start 36.

Abduction at medium term follow-up in one study with high risk of bias, was not significantly better at

6 months, for patients who started early with shoulder exercises compared to patients with a delayed

start. At 2 years follow-up, there was a small but statistically significant difference of 9 degrees (95%

CI: 2 to 16) in favour of an early start 36. In a second study, with unclear risk of bias, patients in the early

mobilisation group also had statistically significant better abduction at six months (mean difference

21 degrees; 95% CI: 13 to 30) 38. In the third study, patients in both groups had declined range

of motion for abduction at 12 months compared to baseline. Although the difference in abduction

between the groups was not statistically significant, it was observed that the early mobilisation group

had worse shoulder function than the delayed mobilisation group, and the 95% CI included a clini-

cally relevant difference (mean difference -8.30, 95% CI: -16.97 to 0.37) 41. Risk of bias in this study

was low for this outcome. The summary estimate for internal rotation at medium-term follow-up was

2.39 degrees (96% CI: -0.14 to 4.92) (Analysis 4.2). Risk of bias in this study was low for this outcome.

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Analysis 4.1Short term range of motion for shoulder internal rotation, early vs delayed start of postoperative shoulder exercises

Analysis 4.2Medium term range of motion for shoulder internal rotation, early vs delayed start of postoperative shoulder exercises

ADL function

Early versus delayed onset of mobilising shoulder exercises after breast cancer treatmentOnly one of the studies reported on ADL function 41. In this study, there were no differences between

early mobilisation and delayed mobilisation in Shoulder Disability Questionnaire score at one year

follow-up (a mean of 1.7 positively scored items versus 1.9 for early and delayed start respectively).

Risk of bias for this outcome was low.

Pain

Early versus delayed onset of mobilising shoulder exercises after breast cancer treatmentOnly one study, with high risk of bias, examined the effects of early versus delayed exercise on pain.

No statistically significant differences were found for pain scores at any follow-up point up to 2 years

in patients who started early with mobilization exercises and patients who had a delayed start of

exercises 36.

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Progressive resistance exerciseOne study with moderate risk of bias for this outcome, examined the effect of progressive resistance

exercise on pain 39. Patients who were engaged in moderate progressive resistance exercise reported

pain significantly more often at 3 months and 6 months, but not at 24 months, compared to a control

group with 6 months of activity restrictions, massage and passive mobilisation: 78% vs 45% at

3 months, 60% vs 36% at 6 months, and 39% vs 34% at 24 months.

Health related quality of life (HRQOL)

Early versus delayed onset of mobilising shoulder exercises after breast cancer treatmentOne study that compared early versus delayed start of exercises reported on HRQoL 41. The average

scores on the Functional Assessment of Cancer Therapy-Breast Trial Outcome Index at 12 months

follow-up were 32.5 for patients who started early with mobilization exercises and 30.9 for patients

who had a delayed start. This difference was smaller than the 5 points difference that was considered

to be clinically important by the authors. The study had low risk of bias for this outcome.

Progressive resistance exerciseThere were no statistically significant differences in the mental and physical summary component

scores of the SF-36 between patients who engaged in progressive resistance exercise and those who

did not increase their activity level, at 12 months follow-up (mean %change in mental component

score: 3.3 versus 3.1, mean %change in physical component score: 6.6 versus 4.1, for exercise and

control group respectively)40,45. Risk of bias in this study was unclear.

Psychosocial morbidity

No data on this outcome

Adverse events

Early versus delayed onset of mobilising shoulder exercises after breast cancer treatmentAlthough this was not specifically described as an adverse event, statistically higher wound drainage

volume was reported in the early mobilisation group compared to the delayed mobilisation group in

one study with low risk of bias for this outcome 41, but not in another study with unclear risk of bias 38.

Absolute values of drainage volume were not reported.

Safety of progressive resistance exercise after breast cancer treatmentSelf-reported (musculoskeletal) injury was assessed with a 1-year recall, using a survey, in one of the

studies. The OR for musculoskeletal injury in the weight lifting group compared to the control group

was 5.6, 95% CI: 0.31 to 26.1 47. Another study noted a 1.5% incidence of musculoskeletal adverse

events (2 patients with a frozen shoulder, one with a supraspinatus tendinopathy), but did not specify

in which of the groups these occurred 39.

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Patient education, monitoring and early interventionIncidence of treatment failure (occurrence of lymphoedema)

There were no studies that evaluated either patient education, or monitoring and early intervention

alone. One study, with high risk of bias, employed an extensive program (‘PMCP’) consisting of patient

education, supervision of exercises and adjustment of self-directed shoulder exercises, and monitoring

of lymphoedema symptoms and early intervention for lymphoedema or shoulder problems if deemed

necessary. The control group received an instruction booklet only. 25.

Absolute numbers of patients at risk in each group at each time point were not available from the

published reports. From a survival curve obtained from the authors of the study, the number of

patients in each group was obtained by subtracting the number of censored patients up to that time

point. 2x2 Tables were then constructed for each follow-up point and risk estimates were calculated.

No statistically significant difference in prevalence of lymphoedema, as defined by a >200ml or

10% change from preoperative volume, was found between the control group and the intervention

group at 1 month (RR: 1.03, 95% CI: 0.07 to 15.8), 3 months (RR: 0.40, 95% CI: 0.12 to 1.37), 6 months

(RR: 0.22, 95% CI: 0.03 to 1.78), 12 months (RR: 0.52, 95% CI: 0.10 to 2.60) and 24 months (RR: 0.34,

95% CI: 0.10 to 1.15). There also were no statistically significant differences at each follow-up point by

any of the other criteria for lymphoedema.

Infection



The recovery pattern for range of motion of shoulder abduction was more favourable for patients

receiving the PMCP intervention than for the control group. Shoulder function in the intervention

group returned to preoperative levels at 3 months, compared to 6 months in the control group

(P=0.001) 25, 44. No statistically significant differences between groups were observed for recovery

pattern of the other shoulder movements (forward flexion, extension, and rotations).

ADL function


Pain


Health related quality of life (HRQoL)


Compression therapyThe effect was studied in a single study in which it was combined with MLD and education. A separate

evaluation of compression therapy is therefore not possible.

Outcome measures in this study included lymphoedema occurrence, pain and health related quality

of life 37. The results are presented in the manual lymph drainage section.

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Discussion Summary of main results

In this systematic review we included ten randomised controlled trials investigating different types of

interventions to reduce the risk of secondary lymphoedema after breast cancer treatment.

Manual Lymph Drainage

Four studies with a total of 385 participants studied the effectiveness of MLD. The main results

are summarized in Summary of findings table 1. The evidence on the effectiveness of MLD on

lymphoedema risk is conflicting. Differences in dosage and administration of the MLD intervention in

the two studies that allowed for evaluation of the effectiveness of MLD only 30,43 may in part account

for the observed differences in effect. It should also be noted however, that compared to the study

that found no effect 30, overall risk of bias in the study that did find statistically significant effects 43 was

higher. In particular, allocation concealment and blinding of outcome assessment were lacking, both

of which are typically associated with larger effect estimates 48.

The results of two other studies on MLD suggest that a combined physiotherapy intervention containing

MLD may reduce the risk of developing lymphoedema compared to education only. The extent to

which MLD accounts for the observed effect cannot be estimated from these studies. Therefore, it is

unclear whether the observed positive effects resulted from the concurrent compression therapy 37 or

exercise therapy 29 rather than MLD or vice versa. Also, the results should be interpreted with caution,

since both trials suffered from risk of bias at several points.

No conclusions can be drawn from the available studies with regard to effects of MLD, with or without

additional intervention, on pain.

The observed effects on shoulder function suggest that MLD combined with exercise memay lead to

better shoulder intervention in the first few weeks after surgery compared to education only. Results

on long term effects were inconsistent. These findings too, should be interpreted with caution due to

the overall low quality of the evidence.

Early versus delayed shoulder mobilisation

Three of the included trials compared early versus delayed full range shoulder exercises after axillary

dissection in a total of 378 breast cancer patients at risk for lymphoedema 36,38,41. The main findings

of these studies are summarized in Summary of findings table 2. The meta-analysis did not yield

a statistically significant elevated risk of lymphoedema after early start of exercises. However, the

point estimate favoured a delayed start. A delayed start of exercises does not seem to have a negative

influence on recovery of shoulder range of motion in medium term, but immediate postoperative start

of exercise leads to better shoulder function in the short term (up to 6 months).

Progressive resistance exercise

Two studies evaluated the safety of progressive resistance exercises after breast cancer surgery

including axillary lymph node dissection, in a total of 351 participants. The results of these studies

(summarized in Summary of findings table 3) support the hypothesis that resistance training does not

increase lymphoedema risk, and may even reduce the risk, provided that lymphoedema symptoms

are closely monitored and adequate treatment is initiated as soon as symptoms become apparent 39,40.

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Overall completeness and applicability of evidence

The number of studies that investigated the effectiveness of a conservative intervention for prevention

of lymphoedema after breast cancer surgery was small, and the type of interventions studied was

limited. None of the included studies investigated the effect of compression therapy only, either

by bandaging, compression sleeves or pneumatic compression, or of lymph taping. There were no

studies evaluating the effect of education or risk-reduction advice compared to no education, or

surveillance and early intervention.

Not all relevant outcome measures were used in the identified studies. ADL functioning in relation to

the affected arm was measured in with a validated self-report measure in only one study 41. Infection

was reported in one study 38, but none of the other studies included it as an outcome measure or

adverse effect. None of the included studies addressed psychosocial morbidity (depression or

anxiety).

Quality of the evidence

The overall quality of the evidence ranged from very low to low, with the exception of the comparison

of progressive resistance training with no exercise, which was graded as moderate (See summary of

findings tables). Lack of blinding accounted for an important part of the reasons for downgrading

the quality of the evidence, as it was judged to be unclear or insufficient in the majority of studies.

The type of interventions under investigation made it very difficult, if not impossible to adequately

blind patients. The impact of this on the observed outcomes is difficult to estimate and may differ

between types of interventions. Since adherence to the assigned intervention was not explicitly

addressed in eight of the studies, this may have introduced bias towards the null hypothesis in superi-

ority trials, and towards the alternative hypothesis in non-inferiority trials.

The definitions used for lymphoedema among the included studies differed, with some studies

reporting on lymphoedema based on several different criteria. Since all of the studies included

a volume criterion to define incident cases, we extracted the results based on this criterion for studies

reporting on several definitions but failing to specify the definition used as the primary outcome.

In one study the primary outcome measure for lymphoedema as defined in the methods section was

not reported 37. Since incident cases of lymphoedema were reported and the authors provided a suffi-

ciently objective criterion, we used this outcome for our analyses. Even though all studies included

a volume criterion, these too differed between studies. Also, different ways of measuring limb volume

were used. These variations added to the observed heterogeneity.

Most studies reported cumulative incidence of lymphoedema, but a number of the studies did this by

reporting the prevalent cases at a certain follow-up point. Since limb volume is variable over time, and

transient episodes of lymphoedema may occur, the reported number of cases observed at a particular

follow-up measurement could be considered point prevalence rather than cumulative incidence.

The use of a priori power calculation was not included in the risk of bias assessment. It should be noted,

however, that sample size calculations were not performed in five studies 29,36-38,43. Power calculations

were performed based on volume differences rather than incidence of lymphoedema in two studies 39,41. All studies reporting a-priori power calculations recruited the targeted number of patients.

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Potential biases in the review process

We performed a comprehensive search in the most relevant databases. We refrained from using

a methodological filter to make sure that no relevant studies would be missed due to misclassification

in the databases. Neither did we impose a language restriction.

The studies identified included both studies with positive findings and studies with negative findings.

Although the number of studies per outcome and intervention was too small to make a formal analysis,

we have found no clues that indicate possible publication bias.

We corresponded with the authors of six studies to obtain additional information on risk of bias related

to study characteristics, and additional outcome data. These data were obtained in most cases, which

makes our review more complete. On the other hand, it also means that some of the details on study

methodology and study results have not yet gone through a peer-review process.

An important limitation of this review was that we included only studies that used lymphoedema as

the primary outcome. As a result of this restriction, studies may have been missed that reported on

lymphoedema as a secondary outcome in trials on exercise, postoperative rehabilitation protocols or

other interventions.

Agreements and disagreements with other studies or reviews

A Cochrane systematic review studied the effect of exercise interventions on upper limb dysfunction

due to breast cancer treatment 51. This review included a number of studies that reported lymphoedema

as a secondary outcome. The reported results with regard to the effects of early versus late start of

exercise on lymphoedema incidence are congruent with our results.

A second systematic review also summarized the evidence on the effectiveness of exercise programmes

on shoulder mobility and lymphoedema 50. While that review included some studies that did not meet

the inclusion criteria of the current review, the authors also conclude that exercise is safe with regard

to lymphoedema risk.

Some of the results that we calculated, based on the available data and using RevMan, were

inconsistent with the results as reported in the source publications. Castro-Sanchez et al. reported

a statistically significant difference in lymphoedema incidence at 8 month follow-up 37. Using the data

as reported, our analysis did not show a statistically significant reduction in lymphoedema risk for

patients receiving a combined intervention of MLD, exercise, scar massage and education, compared

to those receiving education alone (RR=0.13, 95% CI: 0.02 to 1.28, P = 0.07). We have no explanation

for this difference. Conversely, Castro-Sanchez et al. reported a clinically relevant, but statistically

non-significant difference in pain scores (reported P=0.056) whereas in our analysis based on the

reported mean scores and 95%CIs, this difference was statistically significant (calculated P=0.03).

We also do not have an explanation for this difference; it seems unlikely that differences occurred

due to rounding, since confidence intervals were reported precisely (up to 2 decimals). The results as

reported by Box et al. 25 were also not entirely consistent with our calculations based on the available

data, but this did not result in a qualitatively different conclusion.

Authors’ conclusions Implications for practice

The aim of this review was to summarize current evidence and thus provide information that can be

used to guide clinical decisions and guideline development. Unfortunately, the overall low quality

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of the evidence does not allow for firm conclusions on the effect of MLD, compression, exercise or

a combination of these interventions for prevention of upper limb lymphoedema in patients at risk

after breast cancer treatment.

Although the comparison of early versus delayed start of shoulder exercises showed no significant

influence on lymphoedema incidence, the point estimate showed a lower risk of lymphoedema after

delayed start. An early start may result in better range of motion in the short-term compared to a late

start, but this difference disappears from 6 months onward. Other studies have shown that delaying

postoperative shoulder rehabilitation reduces postoperative wound drainage volumes and wound

drainage time, although it does not reduce incidence of seroma formation 49. Clinicians who consider

early recovery of shoulder function as very important may want to consider early onset of exercise.

Otherwise, delaying exercise for a week after the operation could be considered.

Current evidence supports that progressive resistance exercise is safe, and potentially beneficial for

reducing lymphoedema risk in patients treated for breast cancer. The beneficial effects of resistance

training on physical functioning, fatigue and quality of life are well established. Breast cancer survivors

can therefore be actively encouraged to engage in such exercise and can be informed that this will not

increase their risk of developing chronic upper limb lymphoedema, provided that they monitor their

symptoms and see to it that lymphoedema is treated in a timely manner should it occur.

Implications for research

Considering the low number of studies identified, the heterogeneity of interventions applied in these

studies, and the overall low quality of the evidence available to date, future studies are needed.

Many of the included studies in this review did not report on important methodological characteristics

related to risk of bias. Therefore, we would stress the importance of adhering to the CONSORT

guidelines for reporting future clinical trials 51,52.

Using a commonly agreed on criterion for clinically detectable lymphoedema would greatly facil-

itate the interpretation of future studies, but unfortunately no such single criterion currently exists.

Alternatively, future studies could choose to incorporate a number of methods to assess lymphoedema

and report results based on each of those, while clearly specifying the criterion used as the primary

outcome variable. Future studies should preferably use survival analysis to assess the effectiveness

of interventions, as this takes into consideration that even if lymphoedema is not prevented, its onset

may be postponed by the intervention. Including infection, pain, limitations in ADL functioning,

quality of life and mood and adverse events as secondary outcomes is recommended.

Further research is needed to provide more robust evidence on the (combined) interventions as

described in this review, as well as to examine the effectiveness of preventive compression and MLD

as a single intervention, kinesiotaping, and early intervention for subclinical lymphoedema. Although

results from an observational study suggest that early detection by self-examination and subsequent

treatment with conservative interventions may reduce the severity of lymphoedema 27, randomised

controlled trials are needed to confirm these findings. The effect of patient education also needs

further study in randomised controlled trials. While it is generally agreed upon that providing risk-re-

duction advice should be part of routine care after breast cancer treatment, it is currently unclear

whether the benefits outweighs potential harm 26,53,54. In addition, the cost-effectiveness from

a societal perspective should be evaluated for all interventions.

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Table 1 Characteristics and risk of bias of included studies

Bendz 2002

Methods Cluster randomized controlled trial

Participants Women treated for breast cancer with radical mastectomy or quandrantectomy, including ALND, with or without radiotherapy to the chestwall. Mean age 58 (SD 11).

Interventions Intervention group (n=101)Immediate full range exercise supervised by a physical therapist: Preoperative instructions to use the arm as much as comfortable, avoiding lifting and carrying heavier items and avoid forced movements for 14 days. From day 14 forward, full range mobilizing exercises were given to both groups, to be performed 3 times a day. Control group (n=104)Delayed full range exercise: Preoperative instruction on shoulder/arm exercise programme, to be started on the first postoperative day. No abduction or elevation for three days, slowly increasing to elevation and abduction to 90º during 14 days.

Outcomes Primary outcome: Lymphoedema, defined as 10% or greater change in volume of the operated arm, corrected for preoperative differences, using the formula: (volume difference between operated and non-operated arm at baseline - volume difference at follow-up)/ postoperative volume of the operated arm * 100. Secondary outcomes: Range of motion (goniometer) for shoulder flexion, abduction and rotation; Pain (4 point ordinal scale based on visual analogue scale); Hand grip strength (Vigorimeter) Subjective estimation of heaviness and tension (VAS)

Follow up 1 month, 6 months, 24 months follow-up

Country, setting Sweden, University Hospital

Year of conduct 1994-1996

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Risk of bias table for Bendz 2002

BiasAuthors' judgement Support for judgement

Random sequence generation (selection bias)

Unclear risk "Cluster randomisation was used to alternate periods of 4 weeks". The way the sequence of allocation was generated is not described, but earlier randomised studies by the senior author clearly use randomization procedures.

Allocation concealment (selection bias) High risk There is no mention of allocation concealment

Blinding of participants and personnel (performance bias) Measured outcomes

Unclear risk Neither patients nor personnel were blinded for the intervention, but due to the nature of the intervention and the use of cluster randomisation, performance bias seems unlikely.

Blinding of participants and personnel (performance bias) Patient reported outcomes

Unclear risk Neither patients nor personnel were blinded for the intervention, but due to the nature of the intervention and the use of cluster randomisation performance bias seems unlikely.

Blinding of outcome assessment (detection bias) Measured outcomes

High risk Outcome assessors were not blinded.

Blinding of outcome assessment (detection bias) Patient reported outcomes

Unclear risk Patients were not blinded, but the trial was cluster randomised and it seems unlikely that patients self report of pain would be influenced by knowledge of group allocation.

Incomplete outcome data (attrition bias) Measured outcomes

Unclear risk Drop out rates at two years follow-up were twice as high in the early exercise group compared to the delayed exercise group (16 versus 8) and reasons for drop out differed between groups. Also twenty-five patients dropped-out before the first assesment and were not included in any of the subsequent analyses.

Incomplete outcome data (attrition bias) Patient reported outcome

Unclear risk Drop out rates at two years follow-up were twice as high in the early exercise group compared to the delayed exercise group (16 versus 8) and reasons for drop out differed between groups. Also twenty-five patients dropped-out before the first assesment and were not included in any of the subsequent analyses.

Selective reporting (reporting bias) Low risk Outcomes for all variables are reported.

Other bias High risk It is unclear whether the groups were comparable on all relevant risk factors such as number of removed nodes and BMI. There is no explicit statistical consideration for the cluster randomisation.

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Box 2002 Methods Parallel group randomized controlled trial, stratification by surgical procedure

(complete local excision or modified radical mastectomy)

Participants Patients treated surgically for breast cancer (all stages except advanced disease),complete local excision or modified radical mastectomy, including ALND. Mean age (SD) 56 (10.6)

Interventions Intervention Group (n= 32) Physiotherapy Management Care Plan (PMCP). PMCP includes preoperative individual risk assessment, identification of possible risk factors, education on the lymphatic system, education about early signs of lymphoedema and introduction of risk minimisation strategies for identified precipitating factors in the preoperative phase. Postoperatively, outpatient reviews are scheduled (monitoring of shoulder ROM, progression of exercise, provision of LO awareness, individualized intervention if required).

Control Group (n=33)No physiotherapy.

Outcomes Primary outcome:Lymphoedema defined as: 1. Increase of 5cm or more from preoperative sum of circumferences of the arm, operated arm versus non operated side 2. Increase of 200ml or more from preoperative total arm volume difference between the operated and non operated side. 3. Multifrequency Bioelectrical Impedance Measurement: A MFBIA ratio of the arm operated side and and non operated side lower than 95%Conficence Interval from preoperative data, or a 10% change from baseline in the ratio operated arm:unoperated arm

Secondary outcome:Range of motion (goniometer) for shoulder flexion, abduction extension and rotations; Non-validated functional tasks questionnaire

Follow up 1, 3, 6, 12 months

Country, setting Australia, University Hospital


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Risk of bias table for Box 2002 Bias

Authors' judgement Support for judgement

Random sequence generation (selection bias) Low risk Computer generated random number table

Allocation concealment (selection bias) High risk Chronological recruitment with allocation from random number table, without attempts at blinding


Low risk Medical and nursing staff were blinded for group allocation, patients were not. Contamination seems unlikely due to the nature of the intervention.


NA


High risk Outcome measurements were taken by a blinded PT for “as many women as possible”, it is unclear in how many cases this was actually the case.


NA


Low risk There is a 9% loss to follow-up, for reasons unrelated to the outcome


NA

Selective reporting (reporting bias) Low risk All outcomes mentioned in the methods sections are reported

Other bias Unclear risk Women in the treatment group on average had more lymph nodes removed (16 versus 13), more often had level 2 ( 81 versus 64) or 3 ( 16 versus 9)axillary dissection, and more often had radiotherapy (66 versus 49). No sensitivity analysis or adjusted analysis were performed due to the low number of events. Analyses on shoulder function measurements were adjusted for age, number of removed lymph nodes, level of ALND, history of shoulder problems, radiotherapy, chemotherapy and wound infection. C

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Castro-Sanchez 2011 Methods Parallel group randomised controlled trial

Participants Woman aged 30-60, treated for breast cancer (stages not specified) including partial axillary dissection and adjuvant radiotherapy

Interventions Intervention group (n=24)Elastic compression sleeve + manual lymph drainage 5 times a week for 6 months; Lecuc method transthoracical and thoraco-abdominal and manual lymph drainage of the arm.

Control group (n=24)Patient education

Outcomes Primary outcome: Lymphoedema, defined as: Between group mean difference in percentage upper arm volume difference (from circumference measurements) between affected versus non-affected side (not reported).

Secondary outcomes: Incident cases of lymphoedema, defined as > 2cm increase in the circumferential measurements at two adjacent marked points in comparison with the corresponding contralateral arm. Volume of the arm Body composition: fat-free mass (g/kg/d), fat mass (kg), amount of extracellular water (l) as measured with bio impedance measurements. Temperature of the back of the hand, anterior forearm and elbow. Health related quality of life (EORTC-QLQ c30) Pain (10 point visual analogue scale) Functional Shoulder rating scale UCLA (composite score of self report complaints and limitations, ROM measurements and strength measurements)

Follow up 8 months

Country, setting Spain, 2 university hospitals


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Risk of bias table for Castro-Sanchez 2011 Bias



Low risk A computer generated random number table was used.

Allocation concealment (selection bias) Low risk Randomization cards were placed in opaque envelopes that were opened by a therapist who was not involved in baseline assessments.


Unclear risk Participants and personnel were not blinded for the intervention. The risk of contamination is unclear.


Unclear risk Patients and therapist were not blinded for the intervention. The risk of contamination is unclear.


Low risk Outcome assessor was blinded for group allocation


High risk Self report for pain and HRQOL may be affected by patients' knowledge of group allocation.


Low risk There is no loss to follow-up


Low risk There is no loss to follow-up

Selective reporting (reporting bias) High risk Reported incident cases with lymphoedema are based on a different criterion than defined the methods section.

Other bias High risk Baseline imbalance in limbvolume (intervention group: 307ml control group: 378ml) not controlled for in analysis. At baseline, the intervention group had lower scores than the control group for the EORTC QLQ c30 domains of: Physical functioning (114 versus 123), Role functioning (88 versus 96), Social functioning (120 versus 126), Global health (73 versus 87), Constipation (4 versus 11), Diarrhea (44 versus 53), Financial difficulties (5 versus 14). No corrections were made to take these differences into account. The intervention group had more contacts with a therapist, which may reinforce other behaviour such as compliance to exercises and self-care measures

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Cinar 2008 Methods Parallel groups randomised controlled trial

Participants Women (mean age 53, range 29-72), surgically treated for breast cancer with radical modified mastectomy

Interventions Intervention group (n=27) Early postoperative shoulder mobilisation: Shoulder immobilisation on first day, PT supervised active exercises hand and elbow. Gradually increasing shoulder mobilising exercises from day 2 onwards, with passive stretching from day 5 forward. After removal of wound drain 15 sessions of individual PT out-patients setting mobilising and strengthening exercises for the shoulder upper limb. Home based exercise in following 8 weeks, and education on risk reducing behavior. Control group (n=30) Delayed approach to shoulder exercises, starting after removal of the wound drain. Homebased after initial physiotherapist delivered exercise instruction, and education on risk reducing behavior.

Outcomes Primary outcome:

Lymphoedema defined as 1.5-3cm difference in circumference of the treated versus the non-treated upper limb (mild oedema), 3-5 cm difference (moderate), >5 cm difference (severe) Secondary outcome: Non validated questionnaire on functional activities involving the shoulder

Follow up 5 days, 1, 3, 6 months

Country, setting Turkey, hospital

Year of conduct <2007

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Risk of bias table for Cinar 2008 Bias



Unclear risk It is mentioned that treatment allocation was randomised, the method is not stated.

Allocation concealment (selection bias) Unclear risk Not mentioned




NA


Low risk Outcome assessor was blinded to group allocation


NA


Unclear risk No attrition was reported, but the number of patients at follow-up is not reported and there is no consort diagram


Unclear risk

Selective reporting (reporting bias) Low risk All outcomes are reported

Other bias High risk Women in the treatment group on average less often had radiotherapy treatment (10; 37% versus 14; 47% ). The intervention group had more contacts with a therapist, which may reinforce other behaviour such as compliance to exercises and self-care measures.

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De Voogdt 2011

Methods Parallel groups randomized controlled trial, stratification for Body Mass Index and adjuvant radiotherapy

Participants Patients treated for breast cancer (all stages except advanced disease) including ALND

Interventions Intervention group (n=79) Provision of guidelines about prevention of lymphoedema, passive shoulder mobilisation, active shoulder exercises, scar massage and manual lymph drainage (40 one-hour sessions/ week, 3 times/ week, 40 sessions in total)

Control group (n=81) Provision of guidelines about prevention of lymphoedema, passive shoulder mobilisation, active shoulder exercises, scar massage

Outcomes Primary outcome Cumulative incidence of lymphoedema defined as: 1. 200ml or more increase in arm volume difference between healthy and operated side compared to the difference before surgery. 2. Time to develop lymphoedema, by same criterion

Secondary outcome Cumulative incidence of lymphoedema defined as 2 cm or more increase in arm circumference difference at any two adjacent points between healthy and operated side. Time to develop lymphoedema by the same criterion. Point prevalence of lymphoedema using both criteria Point prevalence of subjective lymphoedema Increase of arm volume Health related quality of life (MOS Short Form 36 component scores for physical and mental health) Range of motion of the upper limb (not reported) Lymphscintigraphic examination (not reported) Lymph-SBP questionnaire (not reported)

Follow up 12 months

Country, setting Belgium, University Hospital


95

Risk of bias table for De Voogdt 2011

BiasAuthors' judgement Support for judgement


Low risk Randomization using permuted blocks, stratification for Body Mass Index and adjuvant radiotherapy

Allocation concealment (selection bias) Low risk Allocation to treatment groups was concealed.






Unclear risk Outcome assessors were blinded. However, lymphoedema was assessed at scheduled follow-up measurements or in case of self reported symptoms. Participants were not blinded for the intervention which may have induced differences in propensity towards reporting symptoms based on knowledge of group allocation.


Unclear risk Self report for pain and HRQOL may be affected by patients' knowledge of group allocation.


Low risk There was a very low dropout rate. A sensitivity analysis by the review authors supported the conclusions.


Low risk There was a very low dropout rate.

Selective reporting (reporting bias) Unclear risk Range of motion was measured according to the trial protocol, but not reported. Data were not yet available at the time of writing for this review.

Other bias Unclear risk A higher percentage in the intervention group had level III dissection (43 versus 33%) and a higher percentage had radiotherapy on the axilla (10 versus 6), which may lead to increased risk for the intervention group. C

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Sagen 2009 Methods Parallel group randomised controlled trial.

Participants Women aged 32-75, treated for early stage breast cancer with mastectomy or breast-conserving therapy with ALND (level I en II), with or without radiotherapy, chemotherapy or hormone treatment.

Interventions Intervention (n=104) Supervised physiotherapy consisting of moderate progressive resistance exercise training 2-3 times a week, without restriction in activities. Control (n=100) Restricted activity for the affected limb for 6 months (avoidance of heavy or strenuous activities, carrying or lifting over 3 kg). Supervised physiotherapy consisting of passive manual mobilization, light massage, once a week

Outcomes Primary outcome: Lymphoedema defined as 10% or more increase in Voldiff= (volume of the affected - volume of the heterolateral arm)/volume of the heterolateral arm *100, measured by water displacement volumetry. Secondary outcome: Pain (ordinal scale with three categories, based on visual analogue scale) Sensation of Heaviness (VAS)

Follow up 24 months

Country, setting Norway, 2 University Hospitals


Notes The study question was based on an equivalence hypothesis, but the study was analysed as a superiority trial.

97

Risk of bias table for Sagen 2009 Bias



Low risk Block randomisation by computer program

Allocation concealment (selection bias) Low risk sealed envelopes


Unclear risk Participants and personnel were not blinded. Self reported physical activity scores were lower in the control group than in the intervention group at 3 and 6 months.


Low risk Participants and personnel were not blinded. Self reported physical activity scores were lower in the control group than in the intervention group at 3 months and 6 months.


Unclear risk The blinded outcome assessor was not involved in the interventions performed at the outpatient clinics. However, LO treatment was given whenever necessary during the 6 month intervention and whenever requested between the 6 month and 2 year follow-up. Since patients were not blinded, there may have been differences in reporting symptoms of LO between experimental and control group.


Unclear risk Participants were not blinded. Self reported pain may be affected by participants knowledge of group allocation.


High risk Loss to follow-up in the no activity restriction group was higher compared to the exercise group: 13 vs 10, 14 vs 3 and 36 vs 16 at 3, 6 and 24 months respectively. A last observation carried forward procedure was employed. Since lymphoedema incidence increases over time, this approach is questionable.


High risk More patients were lost to follow-up in group 1 (no activity restriction) compared to group 2: 13 versus 10, 14 versus 3 and 36 versus 16 at 3, 6 and 24 months respectively. A last observation carried forward procedure was employed. Data on 17 patients in group 1 and 15 patients in group 2 were not reported at 3-months follow-up and apparently imputed at six months and two years.

Selective reporting (reporting bias) Low risk All outcomes mentioned in the methods section are reported

Other bias High risk Patients in the activity restriction group also received usual care physiotherapy treatment once a week, which included massage, while patients in the exercise group did not receive massage.The intervention group had more contacts with a therapist, which may reinforce other behaviour such as compliance to exercises and self-care measures. Arm lymphoedema was treated in both groups, both during the intervention period and during follow-up. The figures as reported are based on point-prevalence at follow-up points, not as cumulative incidence. It is therefore unclear how many patients in each group developed lymphoedema at some point during the follow-up that resolved as a result of therapy. This may lead to a biased interpretation of equivalence.

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Schmitz 2010 Methods Parallel groups equivalence trial

Participants Female sex, unilateral BRCA, non-metastatic 1-5 yrs post treatment, BMI<50, currently cancer free, no medical conditions limiting exercise, weight stable, no weight lifting in the year before study entry, no plans for surgery or leave >1 month during study period, not actively trying to loose weight, > 1 LN removed, no current LO

Interventions Intervention group (n=77) 1 year membership to community fitness center, progressive resistance exercises in groups of 2-6, supervised for 13 weeks. Unsupervised for the rest of the study period.Progressive resistance exercises with dumbbells or machines, in 3 sets of 10 reps, increasing weight with the smallest possible increment after completing 2 sessions of 3x10 reps without symptoms of lymphoedema

Control group (n=77) Controls were asked not to change baseline level of exercise during study period,.

Outcomes Primary LO outcome: Lymphoedema defined as: Interlimb difference of >5%, determined by water displacement volumetry: (affected arm volume – unaffected arm volume) / unaffected arm volume

Secondary LO outcomes: Lymphoedema defined as: greatest circumferential difference of >5% and clinician based diagnosis based on CTCAE 3.0 Health related quality of life (SF36) Body image (Body Image and Relationships Scale) Pain (not reported) Musculoskeletal adverse events

Follow up 12 months

Country, setting USA, University Medical Center


99

Risk of bias table for Schmitz 2010 Bias



Low risk Minization balancing for age, NRN, obesity and RT

Allocation concealment (selection bias) Low risk Computerized sequence generation


High risk Patients and personnel were not blinded for the intervention. Although patients in the control group were asked not to change their baseline physical activity level, average self reported physical activity in MET-min/week increased with 370 MET-min/week and 360MET-min/week in the control group. It is unclear whether this involved strength training as well, although there was no significant increase in strength in the control group.


High risk Patients and personnel were not blinded for the intervention


Low risk Outcome observers LO were blinded to group allocation. Participants were asked not to reveal group assignment before measurement sessions.


Unclear risk Participants were not blinded. Self reported HRQoL may be affected by participants knowledge of group allocation.


Low risk The drop-out rate and reasons for drop-out were comparable between groups for the primary outcome, sensitivity analysis (best case/worst case scenario) was performed and findings were robust.


Unclear risk For patient reported outcomes, the attrition rate was 23.3% in the intervention group and 20.8% in the control group at the 12 month follow-up. Time since diagnosis of the evaluable patients in the control group was on average 5 months more than in the intervention group.

Selective reporting (reporting bias) Unclear risk There were no results reported on pain.

Other bias Low risk No other potential sources of bias were identified

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Todd 2008 Methods RCT, parallel groups, single blind

Participants Women with early breast cancer admitted for surgery including ALND

Interventions Intervention group (n=58) Delayed (1 week) full-range shoulder mobilisation exercises. During the first week, exercise was limited to below 90 degrees in all planes of movement. Exercises were to be performed four times per day, until full shoulder movement was restored.

Outcomes Primary outcome: Lymphoedema defined as: 200 ml or more volume difference between the arms on the operated side and the non-operated side. Secondary outcome: Range of motion of the shoulder for flexion, abduction, medial rotation and lateral rotation as measured with a goniometer. HRQOL using the Trial Outcome Index of the Functional Assessment of Cancer Therapy-Breast (FACT-B) Grip strength (JAMAR) Shoulder disability (Shouder disability questionnaire)

Follow up 12 months

Country, setting Two secondary care National Health Service trusts, UK.


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Risk of bias table for Todd 2008 Bias



Low risk Randomisation using random number table and sealed envelopes

Allocation concealment (selection bias) Low risk Women were randomised by an objective third person after completion of baseline measures


Unclear risk Patients and personnel were not blinded for group allocation, but only one patient in the delayed mobilisation group did not receive the allocated intervention.


Unclear risk Patients and personnel were not blinded for group allocation, but only one patient in the delayed mobilisation group did not receive the allocated intervention.


Low risk Outcome observer was blinded, and participants were instructed not to reveal group allocation during follow-up visits


Low risk Patients were not blinded, but HRQOL was assessed at one year follow-up. Given the nature and the duration of the intervention, it seems unlikely that knowledge of group allocation would have influenced patients self report HRQOL.


High risk Results for lymphoedema were imputed using last observation carried forward; sensitivity analysis yields the possibility of a non-significant difference (whereas a significant difference is reported).


Low risk Drop-out was limited

Selective reporting (reporting bias) Low risk All outcome measures mentioned in the methods section are reported.

Other bias Unclear risk It is unclear how many patients in each group were treated for lymphoedema in the period between baseline and follow-up measurements (this was dependent on self report lymphoedema complaints and subsequent clinical evaluation).

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Torres 2010 Methods Parallel groups randomised controlled trial

Participants Women after unilateral breast cancer surgery including ALND, mean age 52.9 (SD 11.6), (N=120). Eighty percent of the women received radiotherapy treatment, 82% chemotherapy

Interventions Intervention group (n=60) Manual Lymph Drainage (thorax, breast, axilla and upper arm), scar massage and exercise therapy (streching, functional activities, active and assisted exercises of the shoulder) for three weeks (3 visits/ week) & education. Control group (n=60) Education only

Outcomes Primary outcome: Lymphoedema, defined as a 2cm or greater increase in the circumference of any two adjecent points compared with measurements in the other arm. Secondary outcome: Pain (VAS); Range of motion of the shoulder; Lymphoedema by other criteria (not reported) Time to event for lymphoedema

Follow up 1, 3, 6 and 12 months (event rates for lymphoedema only available for 12 months)

Country, setting Spain, University hospital

Year of conduct 2005 - 2007

103

Risk of bias table for Torres 2010 Bias



Low risk randomisation was done based on a computer generated randomisation table

Allocation concealment (selection bias) Low risk Patients were enrolled in order of arrival. Randomisation was performed by a different person from the recruiter.




Unclear risk Patients and therapist were not blinded for the intervention. The risk of contamination is unclear.


Unclear risk An independent observer performed all follow-up measurements, however participants were not blinded for the intervention which may have induced differences in propensity towards reporting symptoms based on knowledge of group allocation.This may have biased the estimation of lymphoedema incidence, but not measurements of range of motion of the shoulder.


High risk Self report for pain and HRQOL may be affected by patients' knowledge of group allocation.


Low risk Data is available for all included patients.


Low risk Data is available for all included patients.

Selective reporting (reporting bias) Low risk Data on secondary outcomes are not reported in the publication, but were made available by the researchers.

Other bias High risk Radiotherapy was more often given to patients in the control group (+11%). Trial analysis was per protocol. 3 patients in the control group and one 1 patient in the intervention group who did not receive the allocated intervention were excluded from the analysis. C

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Zimmermann 2012 Methods Parallel groups randomised controlled trial

Participants Women after breast cancer surgery, mean age 67 (range 34 - 81)

Interventions Intervention group:Manual lymphdrainage (Modified Földi and Strössenreuther method), 5 times a week during first 2 weeks, then twice a week from day 14 until 6 months, in addition to standardized physiotherapy (exercises of upper limb and chest). Control group: Self drainage and standardized physiotherapy

Outcomes Primary outcome:Lymphoedema, measured through the water displacement method. Volume of lymphoedema is expressed as the ratio of the difference between arm volume on the operated and nonoperated sides/ armvolume nonoperated side. Cutoff points used for lymphoedema: <5% absence, 5-10% mild, 10-20% moderate >20% substantial. Secondary outcome: Range of motion (goniometer) for shoulder flexion, abduction, extension.

Follow up 2, 7, 14 days, 3 months, 6 months

Country, setting Germany, teaching hospital

Year of conduct 2003 - 2004

105

Risk of bias table for Zimmermann 2012 Bias



Low risk block randomisation using computerized list

Allocation concealment (selection bias) High risk fixed block length, no mention of blinding of allocation




NA


High risk No attempts at blinding were made.


NA


Low risk Outcome is complete for all participants


NA

Selective reporting (reporting bias) Low risk All outcome data is available

Other bias Unclear risk The intervention group had more contacts with a therapist, which may reinforce other behaviour such as compliance to exercises and self-care measures.

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Table 2 Reasons for exclusion of studies Study Reason for exclusion

Ahmed 2006 In both groups patients were included who already had lymphoedema. Allocation was not stratified for presence of lymphoedema, hence no subgroups could be examined.

Anderson 2012 Lymphoedema was not the primary outcome in this study on the effect and safety of a structured exercise program with lymphoedema prevention module on quality of life.

Boccardo, 2009 The intervention was in part non-conservative (microsurgical operation in case of appearance of lymphoedema, as established by lymphscintigraphy).

Box, 2009 Not a primary study, but a synopsis of Todd 2008

Campisi, 2002 The intervention was in part non-conservative (microsurgical lypmhatic-venous anastomoses in patients non responsive to early physical therapy for lymphoedema, as established by lymphscintigrapy).

Chandrakaladharan, 2009 Full text could not be obtained from the author; study was published as an abstract only.

de Rezende, 2006 The study evaluated shoulder function and wound drainage volumes. Lymphoedema was not an outcome.

Hayes 2012 Lymphoedema was not as primary outcome in this study on effect of exercise on quality of life, and the outcome measure used was not sufficiently objective.

Le-Vu, 1997 The primary outcome was seroma formation. Lymphoedema was assessed at some point between 8 and 24 months, but only by self report questionnaire or clinician-based diagnosis.

Oliveira, 2009 The primary outcome was range of motion of the shoulder. Arm circumferences were included as secondary outcome measure. No results on lymphoedema are reported except that there was no statistically significant difference between the groups at all follow-up points.

Sarri, 2010 The primary outcome was lymphatic flow as measured by lymphscintigrapy, as a surrogate endpoint for lymphoedema.

Sisman, 2012 Not a randomised controlled trial

Wang, 2005 No clear and sufficiently objective measure for lymphoedema was defined

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Table 3 Characteristics of ongoing studies

Study id Ben Selvan 2008

Study name The influence of prophylactic application of the class 2 upper limb stockings in carcinoma breast patients in reducing the incidence of Breast cancer related lymph edema

Methods Parallel group single blinded randomised controlled trial, 36 month follow-up, N=178

Participants All patients who need surgery for breast cancer

Interventions Class-2 elastic compression stockings: for a period of three months from the first post operative period, versus no stocking

Outcomes Primary outcome: percentage of reduction in arm volume (circumference measurements) in the study group. Secondary outcome: Incidence of lymphoedema on the 10 th post operative day and at three months follow up

Starting date Registered on 27-11-2008

Contact information Ben Selvan, C.K. Christian medical college, department of surgery, 632004, Vellore, Tamil Nadu India. [email protected]

Registry ID CTRI/2008/091/000249

Study id Pain 2012

Study name Prevention of breast cancer-related lymphoedema following axillary lymph node clearance

Methods Parallel group randomised controlled trial, 36 month follow-up, N=178

Participants Patients who have had axillary node clearance for breast cancer

Interventions Manual lymph drainage, in addition to skin care, compression garments and exercise versus skin care, compression garments and exercise only.

Outcomes Limb volume using circumference measurements, validation of bio-impedance technology

Starting date 01-10-11

Contact information Pain, S, Norfolk & Norwich Univeristy Hospital Coiney Lane Norwich Norfolk NR4 7UY, United Kingdom, [email protected]

Registry ID ACTRN12612000639820

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early physiotherapy including MLD for patients at r isk for secondary upper l imb lymphoedema after breastearly physiotherapy including MLD for patients at r isk for secondary upper l imb lymphoedema after breastcancer treatmentcancer treatment

Patient or populat ion:Patient or populat ion: patients at risk for secondary upper limb lymphoedema after breast cancer treatmentSett ings:Sett ings: Intervention:Intervention: early physiotherapy including MLD

OutcomesOutcomes Il lustrat ive comparative r isks* (95% CI)I l lustrat ive comparative r isks* (95% CI) Relat iveRelat iveeffecteffect(95% CI)(95% CI)

No ofNo ofPart icipantsPart icipants(studies)(studies)

Quali tyQuali tyof theof theevidenceevidence(GRADE)(GRADE)

CommentsComments

Assumedrisk

Corresponding risk

ControlControl Early physiotherapy including MLDEarly physiotherapy including MLD

Time to eventTime to event(Lymphoedema)(Lymphoedema)volumetryFollow-up: 12 months

LowLow HR rangedfrom 0.26to 1.3

270(2 studies) veryvery

lowlow1,2,3

Notestimable

Not estimable

HighHigh

Notestimable

Not estimable

Lymphoedema - shortLymphoedema - shortterm fol low upterm fol low upVolumetryFollow-up: mean 3 months

LowLow RR rangedfrom 0.14to 1.4


lowlow4,5,6

Notestimable

Not estimable

HighHigh

Notestimable

Not estimable

Lymphoedema - mediumLymphoedema - mediumterm fol low upterm fol low upVolumetryFollow-up: 6-12 months



lowlow7,8,9

Notestimable

Not estimable

HighHigh

Notestimable

Not estimable

Pain - medium termPain - medium termfol low-upfol low-upVisual analogue scale. Scalefrom: 0 to 10.Follow-up: 8-12 months

Notestimable

The mean pain - medium term follow-up in theintervention group ranged from 2.4 lower to 0.5higher

164(2 studies)

Shoulder range of motionShoulder range of motionfor abduction - short termfor abduction - short termfol low upfol low upgoniometer. Scale from: 0 to180.Follow-up: 2-4 weeks

The mean shoulder range of motion forabduction - short term follow up in theintervention groups was21.84 higher21.84 higher(13.58 to 30.1 higher)

183(2 studies) lowlow10

Shoulder range of motionShoulder range of motionfor forward f lexion - shortfor forward f lexion - short

The mean shoulder range of motion for forwardflexion - short term follow up in the intervention

183(3 studies)

Summary of Findings Table 1

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early physiotherapy including MLD for patients at r isk for secondary upper l imb lymphoedema after breastearly physiotherapy including MLD for patients at r isk for secondary upper l imb lymphoedema after breastcancer treatmentcancer treatment

Patient or populat ion:Patient or populat ion: patients at risk for secondary upper limb lymphoedema after breast cancer treatmentSett ings:Sett ings: Intervention:Intervention: early physiotherapy including MLD

OutcomesOutcomes Il lustrat ive comparative r isks* (95% CI)I l lustrat ive comparative r isks* (95% CI) Relat iveRelat iveeffecteffect(95% CI)(95% CI)



CommentsComments

Assumedrisk

Corresponding risk

ControlControl Early physiotherapy including MLDEarly physiotherapy including MLD

Time to eventTime to event(Lymphoedema)(Lymphoedema)volumetryFollow-up: 12 months

LowLow HR rangedfrom 0.26to 1.3


lowlow1,2,3

Notestimable

Not estimable

HighHigh

Notestimable

Not estimable

Lymphoedema - shortLymphoedema - shortterm fol low upterm fol low upVolumetryFollow-up: mean 3 months



lowlow4,5,6

Notestimable

Not estimable

HighHigh

Notestimable

Not estimable

Lymphoedema - mediumLymphoedema - mediumterm fol low upterm fol low upVolumetryFollow-up: 6-12 months



lowlow7,8,9

Notestimable

Not estimable

HighHigh

Notestimable

Not estimable

Pain - medium termPain - medium termfol low-upfol low-upVisual analogue scale. Scalefrom: 0 to 10.Follow-up: 8-12 months

Notestimable

The mean pain - medium term follow-up in theintervention group ranged from 2.4 lower to 0.5higher

164(2 studies)

Shoulder range of motionShoulder range of motionfor abduction - short termfor abduction - short termfol low upfol low upgoniometer. Scale from: 0 to180.Follow-up: 2-4 weeks

The mean shoulder range of motion forabduction - short term follow up in theintervention groups was21.84 higher21.84 higher(13.58 to 30.1 higher)

183(2 studies) lowlow10

Shoulder range of motionShoulder range of motionfor forward f lexion - shortfor forward f lexion - short

The mean shoulder range of motion for forwardflexion - short term follow up in the intervention

183(3 studies)

term fol low upterm fol low upgoniometer. Scale from: 0 to180.Follow-up: 2-4 weeks

groups was14.44 higher14.44 higher(7.08 to 21.81 higher)

lowlow10

Shoulder range of motionShoulder range of motionfor abduction - mediumfor abduction - mediumterm term fol low upfol low upgoniometer. Scale from: 0 to180.Follow-up: 6-12 months

Notestimable

The mean shoulder range of motion forabduction - medium term follow up in theintervention group ranged from 3.1 lower to16.9 higher

183(3 studies)

⊕⊝⊝⊝veryverylowlow11,12,13

Shoulder range of motionShoulder range of motionfor forward f lexion -for forward f lexion -medium term fol low upmedium term fol low upgoniometer. Scale from: 0 to180.Follow-up: 6-12 months

Notestimable

The mean shoulder range of motion for forwardflexion - medium term follow up in theintervention group ranged from 0.4 lower to14.3 higher

183(3 studies)

⊕⊝⊝⊝veryverylowlow11,12,13

*The basis for the assumed r iskassumed r isk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding r iskcorresponding r isk(and its 95% confidence interval) is based on the assumed risk in the comparison group and the relat ive effectrelat ive effect of the intervention (and its95% CI).

CI:CI: Confidence interval; RR:RR: Risk ratio; HR:HR: Hazard ratio;GRADE Working Group grades of evidenceHigh qual i ty:High qual i ty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate qual i ty:Moderate qual i ty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change theestimate.Low qual i ty:Low qual i ty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to changethe estimate.Very low qual i ty:Very low qual i ty: We are very uncertain about the estimate.1 A higher percentage in the intervention group had level III dissection (43 vs 33%) and a higher percentage had radiotherapy on the axilla(10 vs 6) in one study (de Voogd 2011), Radiotherapy was more often used in control group in one study (Torres 2010). No blinding ofparticipants and personnel both studies. Per protocol analysis in one study (Torres 2010).2 No evidence of effect in one study (deVoogd 2011), large effect in one study (Torres 2010). Contradicting point estimates.3 No meta analysis was possible due to statistical heterogeneity, 95%CI includes clinically relevant values in both directions in one study(de Voogd, 2011)4 No allocation concealment in one study (Zimmermann 2012), no blinding of outcome assessment in one study (Zimmermann 2011). 5 No evidence of effect in one study (de Voogd 2011), large effect in the second study (Zimmermann 2012).6 No meta-analysis was possible, one study with a very large confidence interval (Zimmermann 2012) one study with small confidenceinterval (de Voogd 2011)7 No allocation concealment in one study (Zimmermann 2012), selective outcome reporting in one study (Castro-Sanchez 2011), Noblinding of outcome assessment in 3 studies (Castro-Sanchez 2011, Torres 2010, Zimmermann 2011). No intention-to-treat analysis in ondestudy (Torres 2010), groups not comparable at baseline in one study (Castro-Sanchez 2011, Torres 2010), treatment of groups differedapart from assigned intervention (Castro-Sanchez 2011, Torres 2010).8 strong statistical heterogeneity9 Broad 95% confidence intervals including clinically relevant effects in both directions in three studies (Castro-Sanchez 2011, Torres 2011,de Voogd 2011).10 No allocation concealment in one study (Zimmermann 2012) No blinding of outcome assessment in both studies. No intention-to-treatanalysis in onde study (Torres 2010), treatment of groups differed apart from assigned intervention (Torres 2010).11 No allocation concealment in one study (Zimmermann 2012) No blinding of outcome assessment in both studies. No intention-to-treatanalysis in onde study (Torres 2010), groups not comparable at baseline in one study for radiotherapy treatment (Castro-Sanchez 2011,Torres 2010), treatment of groups differed apart from assigned intervention (Torres 2010).12 Large effect in favour of intervention in one study (Zimmermann 2012), small non-significant effect favouring the control group in anotherstudy (Torres 2010)13 Broad 95% CI in one none-significant study includes potentially clinically relevant effects in both directions (Torres 2010).

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Early shoulder mobil ising exercises compared to Delayed shoulder mobil ising exercises for patientEarly shoulder mobil ising exercises compared to Delayed shoulder mobil ising exercises for patientsurgically treated for breast cancersurgically treated for breast cancer

Patient or populat ion:Patient or populat ion: patients at risk for secondary upper limb lymphoedema after breast cancer treatment Sett ings:Sett ings: HospitalIntervention:Intervention: early shoulder mobilising exercisesComparison: Comparison: delayed shoulder mobilising exercises

OutcomesOutcomes Il lustrat ive comparative r isks* (95% CI)I l lustrat ive comparative r isks* (95% CI) Relat iveRelat iveeffecteffect(95%(95%CI)CI)



CommentsComments

Assumed risk Corresponding risk

Delayed shoulderDelayed shouldermobil ising exercisesmobil ising exercises

Early shoulder mobil isingEarly shoulder mobil isingexercisesexercises

Lymphoedema -Lymphoedema -medium term fol lowmedium term fol lowupupVolumetry/CircumferenceFollow-up: 6-12 months

LowLow RR 0.59RR 0.59(0.33 to1.06)


lowlow1,2,3

5 per 1005 per 100 3 per 1003 per 100(2 to 5)

HighHigh

20 per 10020 per 100 12 per 10012 per 100(7 to 21)

Shoulder range ofShoulder range ofmotion for abductionmotion for abduction- short term fol low- short term fol lowupupgoniometer. Scale from:0 to 180.Follow-up: 1 months

Not estimable The mean shoulder range of motionfor abduction - short term follow upin the intervention group rangedfrom 6 to 43 higher


lowlow1,4

Shoulder range ofShoulder range ofmotion for abductionmotion for abduction- medium term fol lowmedium term fol lowupupgoniometer. Scale from:0 to 180.Follow-up: 6-12 months

Not estimable The mean shoulder range of motionfor abduction - medium term followup in the intervention group rangedfrom 8.3 lower to 21.3 higher


lowlow5,6,7

Shoulder range ofShoulder range ofmotion for forwardmotion for forwardflexion - short termflexion - short termfol low upfol low upgoniometer. Scale from:0 to 180.Follow-up: 1 months

Not estimable The mean shoulder range of motionfor forward flexion - short term followup in the intervention group rangedfrom 7 to 35.7 higher

262(2 studies) lowlow1,8

Shoulder range ofShoulder range ofmotion for forwardmotion for forwardflexion - mediumflexion - mediumterm fol low upterm fol low upgoniometer. Scale from:0 to 180.Follow-up: 6-12 months

Not estimable The mean shoulder range of motionfor forward flexion - medium termfollow up in the intervention groupranged from 0.6 lower to 5 higher


lowlow5,6,9

Shoulder range ofShoulder range ofmotion for externalmotion for externalrotat ion - short termrotat ion - short termfol low upfol low upgoniometer. Scale from:0 to 90.Follow-up: 1 months

Not estimable The mean shoulder range of motionfor external rotation - short termfollow up in the intervention groupranged from 1 to 15 higher


lowlow1,8,10

Shoulder range ofShoulder range of Not estimable The mean shoulder range of motion 378


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Early shoulder mobil ising exercises compared to Delayed shoulder mobil ising exercises for patientEarly shoulder mobil ising exercises compared to Delayed shoulder mobil ising exercises for patientsurgically treated for breast cancersurgically treated for breast cancer

Patient or populat ion:Patient or populat ion: patients at risk for secondary upper limb lymphoedema after breast cancer treatment Sett ings:Sett ings: HospitalIntervention:Intervention: early shoulder mobilising exercisesComparison: Comparison: delayed shoulder mobilising exercises

OutcomesOutcomes Il lustrat ive comparative r isks* (95% CI)I l lustrat ive comparative r isks* (95% CI) Relat iveRelat iveeffecteffect(95%(95%CI)CI)



CommentsComments

Assumed risk Corresponding risk

Delayed shoulderDelayed shouldermobil ising exercisesmobil ising exercises

Early shoulder mobil isingEarly shoulder mobil isingexercisesexercises

Lymphoedema -Lymphoedema -medium term fol lowmedium term fol lowupupVolumetry/CircumferenceFollow-up: 6-12 months

LowLow RR 0.59RR 0.59(0.33 to1.06)


lowlow1,2,3

5 per 1005 per 100 3 per 1003 per 100(2 to 5)

HighHigh

20 per 10020 per 100 12 per 10012 per 100(7 to 21)

Shoulder range ofShoulder range ofmotion for abductionmotion for abduction- short term fol low- short term fol lowupupgoniometer. Scale from:0 to 180.Follow-up: 1 months

Not estimable The mean shoulder range of motionfor abduction - short term follow upin the intervention group rangedfrom 6 to 43 higher


lowlow1,4

Shoulder range ofShoulder range ofmotion for abductionmotion for abduction- medium term fol lowmedium term fol lowupupgoniometer. Scale from:0 to 180.Follow-up: 6-12 months

Not estimable The mean shoulder range of motionfor abduction - medium term followup in the intervention group rangedfrom 8.3 lower to 21.3 higher


lowlow5,6,7

Shoulder range ofShoulder range ofmotion for forwardmotion for forwardflexion - short termflexion - short termfol low upfol low upgoniometer. Scale from:0 to 180.Follow-up: 1 months

Not estimable The mean shoulder range of motionfor forward flexion - short term followup in the intervention group rangedfrom 7 to 35.7 higher

262(2 studies) lowlow1,8

Shoulder range ofShoulder range ofmotion for forwardmotion for forwardflexion - mediumflexion - mediumterm fol low upterm fol low upgoniometer. Scale from:0 to 180.Follow-up: 6-12 months

Not estimable The mean shoulder range of motionfor forward flexion - medium termfollow up in the intervention groupranged from 0.6 lower to 5 higher


lowlow5,6,9

Shoulder range ofShoulder range ofmotion for externalmotion for externalrotat ion - short termrotat ion - short termfol low upfol low upgoniometer. Scale from:0 to 90.Follow-up: 1 months

Not estimable The mean shoulder range of motionfor external rotation - short termfollow up in the intervention groupranged from 1 to 15 higher


lowlow1,8,10

Shoulder range ofShoulder range of Not estimable The mean shoulder range of motion 378motion for externalmotion for externalrotat ion - mediumrotat ion - mediumterm fol low upterm fol low up11

goniometer. Scale from:0 to 90.Follow-up: 6-12 months

for external rotation - medium termfollow up in the intervention groupranged from 1 lower to 8 higher

(3 studies) veryverylowlow5,12

Shoulder range ofShoulder range ofmotion for internalmotion for internalrotat ion - short termrotat ion - short termfol low upfol low upgoniometer. Scale from:0 to 90.Follow-up: 1 months

The mean shoulder rangeof motion for internalrotation - short term followup in the control groupswasdegreesdegrees

The mean shoulder range of motionfor internal rotation - short termfollow up in the intervention groupswas0.23 higher0.23 higher(2.21 lower to 2.67 higher)

262(2 studies)

⊕⊕⊝⊝

lowlow1

Shoulder range ofShoulder range ofmotion for internalmotion for internalrotat ion - mediumrotat ion - mediumterm fol low upterm fol low upgoniometer. Scale from:0 to 90.Follow-up: 6-12 months

The mean shoulder range of motionfor internal rotation - medium termfollow up in the intervention groupswas2.4 higher2.4 higher(0.14 lower to 4.9 higher)

378(3 studies)

⊕⊕⊝⊝

lowlow5


CI:CI: Confidence interval; RR:RR: Risk ratio;GRADE Working Group grades of evidenceHigh qual i ty:High qual i ty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate qual i ty:Moderate qual i ty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change theestimate.Low qual i ty:Low qual i ty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to changethe estimate.Very low qual i ty:Very low qual i ty: We are very uncertain about the estimate.

1 No allocation concealment in one study (Bendz 2002), no blinding of outome assessment in one study (Bendz 2002), No explicit statisticalconsideration for cluster randomisation (Bendz 2002), unclear risk of bias for allocation procedure and concealment and attrition in onestudy (Cinar 2008), unequal treatment of groups besides intervention in one study (Cinar).2 Large and statistically significant effect in favour of intervention in one study(Todd 2008), statistically non-significant effecst in favour ofcontrol group in another study (Bendz 2002). 3 Broad 95% confidence interval including clinically relevant effect in non-significant meta-analysis. 4 small and non significant effect in one study (Bendz 2002), large statistically significant effect in another study (Cinar 2008). Data poolingcould not be performed due to significant statistical heterogeneity. 5 No allocation concealment in one study (Bendz 2002), no blinding of outome assessment in one study (Bendz 2002), high risk of attritionbias in one study (Todd 2008), no explicit statistical consideration for cluster randomisation (Bendz 2002), unclear risk of bias for allocationprocedure and concealment and attrition in one study (Cinar 2008), unequal treatment of groups besides intervention in one study (Cinar).6 No metaanalysis could be performed due to significant statistical heterogeneity, with contradicting effect estimates in three studies: (Bendz2002; Cinar 2008; Todd 2008)7 Very broad 95% confidence intervals including both neutral values and large clinically relevant effects in two studies (Bendz 2002, Todd2008). Data pooling was not possible due to significant statistical heterogeneity.8 No data pooling was possible due to significant statistical heterogeneity, but point estimates are in favour of early mobilisation andstatistically significant in both studies (Bendz 2002, Cinar 2008).9 95% confidence interval includes both neutral and potentially clinically relevant values in one study (Todd 2008), and a small clinicallyirrelevant effect in the lower boundary of the CI in a second study (Bendz 2002).10 95%CI in one study included both small and very large effect (Cinar 2008).11 Pooled data are from 6 month follow up (Bendz 2002) and 12 month follow up (Todd 2008).12 Two studies with non-significant effect with point estimate favouring delayed exercise (Bendz 2002, Todd 2008), one studie with a largestatistically significant effect favouring early exercise (Cinar 2008).

112

progressive resistance exercise for patients at r isk for secondary upper l imb lymphoedema after breastprogressive resistance exercise for patients at r isk for secondary upper l imb lymphoedema after breastcancer treatmentcancer treatment

Patient or populat ion:Patient or populat ion: patients at risk for secondary upper limb lymphoedema after breast cancer treatmentSett ings:Sett ings: Intervention:Intervention: progressive resistance exercise

OutcomesOutcomes Il lustrat ive comparative r isks* (95%Il lustrat ive comparative r isks* (95%CI)CI)

Relat iveRelat iveeffecteffect(95% CI)(95% CI)


Quali ty of theQuali ty of theevidenceevidence(GRADE)(GRADE)

CommentsComments

Assumedrisk

Corresponding risk

ControlControl Progressive resistanceProgressive resistanceexerciseexercise

LymphoedemaLymphoedemaVolumetryFollow-up: 12-24months

LowLow RR 0.58 RR 0.58 (0.3 to 1.13)

351(2 studies) moderatemoderate1

0 per 1000 per 100(0 to 0)

HighHigh

17 per17 per100100

10 per 10010 per 100(5 to 20)


CI:CI: Confidence interval; RR:RR: Risk ratio;GRADE Working Group grades of evidenceHigh quali ty:High quali ty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate qual i ty:Moderate qual i ty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change theestimate.Low quali ty:Low quali ty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to changethe estimate.Very low quali ty:Very low quali ty: We are very uncertain about the estimate.1 Both studies did not blind participants for the intervention. In one study,activity levels over time increased in both experimental and controlgroup, despite requests to the control group not to increase activity levels during study period, One study (Sagen 2009) had more patientslost to follow up in the experimental group, data were imputed using last observation carried forward. Contact with a physiotherapist wasmore frequent in the experimental group in one study, which may reinforce self-care/ risk reducing behaviour (Sagen 2009).

AcknowledgementsThe authors would like to thank Faridi van Jetten, Academic Medical Center - Univeristy of Amsterdam

for her help with developing the search strategy; Chen Xiao Chen, BM, University of Winsconsin-

Madison - School of Nursing, and Anna Miquel Cases, The Netherlands Cancer Institute for their

help with translation of the non-English language studies; all authors of included studies who were

very helpful by clarifying details about the study and providing additional data; the Cochrane Breast

Cancer Group and especially Dr. Melina Willson, editor, for her support with developing this review

and Fergus Tai for his help with the searches.


113

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47. Brown JC, Troxel AB, Schmitz KH. Safety of Weightlifting Among Women with or at Risk for Breast Cancer-Related Lymphedema: Musculoskeletal Injuries and Health Care Use in a Weightlifting Rehabilitation Trial. Oncologist 2012;17:1120–8.

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APPENDICES CH. 5Search strategies used for ‘Conservative interventions for preventing clinically detectable upper-limb

lymphoedema in patients who are at risk of developing lymphoedema after breast cancer therapy

1. MEDLINE via Pubmed (1980 to present) (“breast neoplasms”[MeSH] OR breast cancer*[tiab] OR breastcancer*[tiab] OR breast tumor-

*[tiab] OR breast tumour*[tiab] OR mammary neoplasm*[tiab] OR mammary carcinoma*[tiab] OR

breast neoplasm*[tiab] OR breast carcinoma*[tiab] OR breast malignan*[tiab] OR breast metasta-

s*[tiab] OR mammary malignan*[tiab] OR mammary metastas*[tiab]) AND (lymphoedema[tiab] OR

“lymphedema”[MeSH Terms] OR lymphedema[tiab] OR lymphatic edema[tiab] OR oedema[tiab] OR

“edema”[MeSH Terms] OR edema[tiab] OR swelling[tiab] OR elephantias*[tiab]) AND (prevent*[tiab]

OR “prevention and control”[Subheading] OR “Preventive Health Services”[Mesh] OR “Early

Diagnosis”[Mesh] OR “Risk”[Mesh] OR risk*[tiab] OR “Risk Reduction Behavior”[MAJR] OR reduc-

ing[tiab] OR “Probability”[Mesh] OR restrict*[tiab] OR prevalence*[tiab] OR “Prevalence”[Mesh])

2. EMBASE via Ovid (1980 to present)

1. exp breast cancer/ or (breast cancer* or breastcancer* or breast tumor* or breast tumour* or mammary neoplasm* or mammary carcinoma* or breast neoplasm* or breast carcinoma*).ti,ab.

2. lymphedema/ or elephantiasis/ or (lymphoedema or lymphedema or lymph edema or lymphatic edema or oedema or edema).ti,ab.

3. prevention/ or early diagnosis/ or risk/ or *risk reduction/ or probability/ or prevalence/ or prediction/ or (prevent* or risk* or reducing or restrict* or prevalence*).ti,ab.

4. 1 and 2 and 3

5. limit 4 to embase

3 WHO ICTRP Search Portal Basic Searches:

1. Conventional interventions for preventing clinically detectable upper-limb lymphoedema in patients who are at risk of developing lymphoedema after breast cancer therapy

2. Lymphoedema AND prevent*

3. Lymphedema AND prevent*

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Advanced Searches:

1. Title: Conventional interventions for precenting clinically detectable upper-limb lymphoedema in patients who are at risk of developing lymphoedema after breast cancer therapy. Recruitment Status: ALL

2. Condition: breast cancer AND (lymphoedema OR lymphedema OR lymphatic oedema OR lymphatic edema OR oedema OR edema) Intervention: prevention OR control OR early diagnosis OR risk reduction behavior OR exercise OR patient education OR early intervention OR monitoring OR compression therapy OR manual lymph drainage OR lymph taping OR kinesiotape

3. Recruitment Status: ALL

4 The Cumulative Index to Nursing and Allied Health Literature (CINAHL) via EBSCO (1980 to present)

S4 S1 and S2 and S3

S3

( ( (MH “Early Diagnosis+”) or (MH “Relative Risk”) or (MH “Probability”) or (MH “Prevalence”)

) or ( ( ( TI restrict* OR AB restrict* ) or ( TI prevalence* OR AB prevalence* ) ) or ( ( TI prevent*

OR AB prevent* ) or ( TI risk* OR AB risk* ) or ( TI reducing OR AB reducing ) ) ) ) or ( TI predict*

or AB predict* ) or (MH “Risk Factors+”)

S2

( (MH “Lymphedema+”) or ( ( TI lymphoedema or AB lymphoedema ) or ( TI lymphedema or

AB lymphedema ) or ( TI lymph edema or AB lymph edema ) ) or ( ( TI lymphatic edema or

AB lymphatic edema ) or ( TI oedema or AB oedema ) or ( TI edema or AB edema ) ) ) or ( ( TI

swelling or AB swelling ) or ( TI elephantias* or AB elephantias* ) )

S1

(MH “Breast Neoplasms+”) or ( ( TI breast cancer* or AB breast cancer* ) or ( TI breastcancer*

or AB breastcancer* ) or ( TI breast tumor* or AB breast tumor* ) ) or ( ( TI breast tumour* or

AB breast tumour* ) or ( TI mammary neoplasm* or AB mammary neoplasm* ) or ( TI mammary

carcinoma* or AB mammary carcinoma* ) or ( TI breast neoplasm* or AB breast neoplasm* ) or

( TI breast carcinoma* or AB breast carcinoma* ) )

5 Physiotherapy Evidence Database (PEDro) via http://pedro.org.au (1980 to present)

1. Abstract and title: cancer

2. Problem: oedema

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6 PsycINFO via Ovid (1980 to present)

1. lymphoedema.id. or (lymphoedema or lymphedema or lymphatic edema or oedema or edema or swelling or elephantias*).ti,ab.

2. risk factors/ or risk factors.id. or (prevent* or risk* or reducing or restrict* or prevalence*).ti,ab.

3. breast neoplasms/ or breast cancer.id. or (breast cancer* or breastcancer* or breast tumor* or breast tumour* or mammary neoplasm* or mammary carcinoma* or breast neoplasm* or breast carcinoma* or breast malignan* or breast metastas* or mammary malignan* or mammary metastas*).ti,ab.

4. 1 and 2 and 3

7 CENTRAL

1. MeSH descriptor: [Lymphedema] explode all trees

2. lymphoedema* or lymphedema* or lymphatic oedema* or lymphatic edema* or oedema* or edema* or swelling

3. MeSH descriptor: [Elephantiasis] explode all trees

4. #1 or #2 or #3

5. MeSH descriptor: [Breast Neoplasms] explode all trees

6. breast neoplasm or breast cancer or breast tumour or breast tumor or breast carcinoma

7. #5 or #6

8. #4 and #7

9. ‘prevention and control’ or prevent* or control or early diagnosis or risk reduction behavior or exercise or patient education or early intervention or monitoring or compression therapy or manual lymph drainage or lymph taping or kinesiotape

10. #8 and #9

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CHAPTER 6Impact of shoulder complaints after neck dissection on shoulder disability and quality of life

Martijn M Stuiver1

Cornelis P van Wilgen 2,5,7

Erlijn M de Boer1

Cees JT de Goede 3

Muriel Koolstra 3

Anita van Opzeeland4

Piet Venema4

Margriet W Sterken5

Andrew Vincent6

Pieter U Dijkstra 5,7,8.

1. Department of Physiotherapy, The Netherlands Cancer Institute- Antoni van Leeuwenhoek Hospital, Amsterdam

2. Pain Centre; Department of Anesthesiology, University Medical Centre Groningen, University of Groningen School of Health Care Studies, Hanze University Groningen, University of Applied Sciences, Groningen

3. Department of Physiotherapy, Free University Medical Center, Amsterdam4. Department of Physiotherapy, Medical Center Leeuwarden5. Center for Rehabilitation, University Medical Center Groningen University of Groningen6. Department of Biostatistics, The Netherlands Cancer Institute-

Antoni van Leeuwenhoek Hospital, Amsterdam7. Dept of Oral and Maxillofacial Surgery, University Medical Center Groningen, University of Groningen.8. Northern Centre for Health Care Research, University of Groningen

Published in Otolaryngol Head Neck Surg. 2008 Jul;139(1):32–9.

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ABSTRACT Objective To explore relationships between shoulder complaints after neck dissection, shoulder disability and

quality of life. To find clinical predictors for mid- to long-term shoulder disability.

Study designProspective

Patients and methodsShoulder pain, shoulder mobility and shoulder droop, as well as scores on shoulder disability

questionnaire and RAND-36 (quality of life), were measured at baseline, discharge (T1) and 4 months

postoperatively (T2) on 139 patients admitted for neck dissection to major head and neck centers in

the Netherlands.

ResultsShoulder mobility was significantly decreased at T1 and did not improve. Significant relationships

between shoulder function, shoulder disability score, and RAND-36 domains were found. Two clusters

of clinical symptoms could be identified as independent predictors for shoulder disability.

ConclusionsObjective deterioration in shoulder function after neck dissection is associated with perceived

shoulder disability and related to physical functioning and bodily pain. Predictors for shoulder

disability can be found.

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IntroductionShoulder complaints after radical neck dissection have been described by Ewing as early as 1952

as “the shoulder syndrome” consisting of shoulder pain, restricted range of motion, shoulder

droop, scapular winging, and abnormal electromyographical findings 1. Reported prevalences of

shoulder complaints range from 4 to 100 percent after radical neck dissection 18 to 61 percent after

modified dissections and 29-52 percent after selective dissections 2-4. Risk factors for shoulder pain

and restricted range of motion are sacrifice of the accessory nerve and plastic reconstructions with

myocutaneous flaps 5. Several explanations have been proposed to account for shoulder pain and

loss of range of motion, including adhesive capsulitis, paralysis of the m. trapezius pars descendens,

myofacial trigger points, acromio-clavicular (AC) or sterno-clavicular (SC) luxations, and neuropathic

disorders 3, 6-8. Few prospective studies assessing shoulder shoulder complaints after neck dissection

have been performed 5, 9, 10.

In a recent prospective clinical study, incident cases of shoulder pain were identified and risk factors

for shoulder pain after neck dissection were determined 5. A limitation of that study was that follow

up ended at the day of dismissal from the hospital, leaving unclear how shoulder complaints after

neck dissection develop over time. Perceived shoulder disability was measured in a prospective study.

Patients after neck dissection all reported worse shoulder function after 6 and 12 months 11. However,

in this study no objective findings from a physical examination were used, nor were interactions

between shoulder disability and other domains of quality of life studied. It seems likely that shoulder

complaints will influence health related quality of life (HRQOL).

Exercise programs seem to have positive effects on shoulder complaints and shoulder disability 12,13.

These programs consist of intensive exercise therapy. However, patients have to cope with other

problems besides shoulder complaints in the first months after neck dissection, such as the burden of

adjuvant therapy or psychosocial problems. It could be argued that the first months after surgery are

not the most suitable time to start intensive exercise therapy. It would therefore be useful to identify

clinical risk factors for mid-to long-term shoulder disability so that benefits can be balanced against

costs for individual patients. The primary aim of our study was to explore the development of shoulder

function disorders in the post clinical phase and their relationship to perceived shoulder disability and

HRQOL. Secondary aim was to find clinical predictors for mid-long term shoulder disability in activities

of daily living, in terms of objective findings from physical examination and patient characteristics.

METHODSPatients

Four Dutch head and neck centers participated in this multi-center study; The Netherlands Cancer

Institute – Antoni van Leeuwenhoek Hospital (NKI-AVL), Leeuwarden Medical Centre, University

Medical Center Groningen and VU University Medical Center. Between 2003 and 2005 a sample of

139 patients was included in our study. Inclusion criteria were: age ≥18 years and admission for neck

dissection. Patients who had shoulder pain on the side of the neck dissection in the week before

surgery were excluded. Patients were also excluded if they lacked basic proficiency in Dutch or when

they had serious cognitive or psychiatric disorders.

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Variables measured and treatment of patients

Because shoulder function and quality of life assessment are part of routine healthcare evaluation

in the participating hospitals, approval of a medical ethics committee was not necessary. However,

verbal informed consent regarding the use of these measurements for the purposes of this study

was obtained and documented in the case record form for all patients. All data were anonymized for

confidentiality. Approval of publication of the study results was granted retrospectively by NKI-AVL

Medical Ethics Committee. Socio-demographic data and information on tumour type, localization,

staging, type and extent of surgery, type of reconstructive surgery, side, type and extent of neck

dissection (radical, modified, or selective neck dissection, structures preserved) 14, radiotherapy and

use of pain medication were derived from medical records. The day before surgery (T0), patients

completed the shoulder disability questionnaire (SDQ) and the RAND36, a questionnaire that assesses

health-related quality of life. The SDQ is a validated 16-item questionnaire describing a variety of

situations during which the patient might experience shoulder problems (pain or restricted range of

motion). The calculated score ranges from 0, indicating no disability, to 100 points, indicating high

disability 15. The RAND36 is a validated 36-item questionnaire, very similar to the SF-36 16.

Active range of motion (AROM) was assessed for shoulder forward flexion (FF) and abduction (ABD),

and for cervical rotation and extension. These values were obtained using an inclinometer (Mediclino®)

according to a standardized measurement protocol 17. Presence or absence of shoulder droop was

recorded. Postoperative physiotherapy started immediately after removal of the wound drain and was

applied according to guidelines that were developed previously and comprise mild passive and active

exercises to improve and maintain shoulder mobility and muscle function, active exercises to regain

mobility of the neck, and patient education 17.

At discharge from the hospital (T1) shoulder function and shoulder droop were evaluated again.

Current shoulder pain was measured using a numeric rating scale (NRS) from 0 to 10, with 0 indicating

no pain at all and 10 indicating the worst imaginable pain. The shoulder joint was tested for pain

during external rotation. Physiotherapy was continued in primary care setting if winging of the scapula

was present during active movements of the shoulder, if pain scores were ≥ 4 on the NRS, if the extent

of loss of AROM was greater than would be expected on the basis of the surgery, or if there were other

reasons to expect an increased risk for developing serious shoulder complaints. The physiotherapists

to whom the patients were referred were informed in writing about type of surgery and the preferred

therapy. Other patients were given home exercises or were seen regularly, but with a low frequency,

on an outpatient basis. After approximately four months (T2), during a regular control visit to their

treating physician in the hospital, patients filled out the RAND36 and SDQ. In addition, the physical

examination of shoulder and neck was repeated.


Descriptive statistics were calculated for relevant demographic and clinical variables, including

scores calculated from quality of life and SDQ. For variables that were normally distributed, mean

and standard deviation are presented. For variables that were not normally distributed, median and

interquartile range (IQR) are presented, and 95% confidence intervals were calculated by bootstrap

resampling using 5000 iterations. Missing data from predictor values were imputed by using multiple

imputation (AregImpute from Hmisc S-plus library). A binary logistic regression model was constructed

to determine if the SDQ observations missing at T2 were related to any of the predictor variables.

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An ordinary least squares regression model was constructed to examine the relationships between

SDQ at T2 and the predictor variables. In both models, the estimates and variance-covariance matrix

were adjusted to account for the imputation of the missing predictor values. In the linear model,

a square-root transformation of the SDQ values was employed. Because of high correlation, predictor

variables were clustered by using the square of Spearman’s rho (Varclus from Hmisc S-plus library).

A threshold of 0.5 was set to determine the clusters, and the joint influence per cluster was examined.

For all tests, a 2-sided p ≤ 0.05 was considered statistically significant. All statistical analyses were

performed with S-Plus 6.2 for Windows (Insightful Corporation, Seattle).

Table 1Descriptive statistics of population under study and characteristics of therapy performed

Variables % number

Gender

Male 62 73

Female 38 45

Age

mean (SD) 58 (12.6)

Preoperative radiotherapy to the neck

Yes 12 14

Chemoradiation 2 3

No 86 101

Side of dissection

Left 42 49

Right 39 46

Both sides 19 23

Type of dissection

Radical 13 15

Modified radical* 44 52

Selective 43 51

Preservation of cervical branches

Yes 25 29

No 23 27

Unknown 53 62

Reconstructive surgery

No reconstruction 64 76

Pectoralis major myocutaneous Flap 16 19

Radial Forearm Flap 7 8

Fibula 3 3

Other reconstruction 10 12

Postoperative radiotherapy (n=87) 68 59

* In three cases the accessory nerve was sacrificed despite modified dissection

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Results

Descriptive statistics

Of 139 enrolled patients, 118 (85%) completed the study. One patient died during follow up, three had

a recurrence, one patient refused further participation, one patient suffered a stroke, three patients

did not return their questionnaires, and 12 patients were lost to follow up for unknown reasons.

Median length of follow up was 16 weeks (IQR 14 ; 19). Descriptive statistics of the population under

study, preoperative radiotherapy, type and extent of operation and reconstructive surgery, and type

and stage of tumour, are summarized in Table 1 and 2.

Table 2 TN classification on the basis of pathology report

N0 N1 N2 N3 Total

4 3 1 0 8

Tx

T1 13 2 5 1 21

T2 23 6 8 1 38

T3 7 3 7 0 17

T4 7 2 7 0 16

Total 54 16 28 2 100*

* TNM classification is not used for melanoma’s (n=17). Data was missing for one patient

Information about shoulder pain at dismissal from the hospital was available for 110 patients. At T1, 55

percent of patients experienced shoulder pain. Between T1 and T2, 66.3 percent of patients had no

change in pain, 14.6 percent exhibited an increase in pain, and 19.0 percent had a reduction in pain.

At T2, shoulder pain was present in 48 percent of cases (Table 3). In total, 31 patients in the current

study had a baseline score on the shoulder disability questionnaire (SDQ) above zero, although

we excluded patients who reported they had shoulder complaints in the week before surgery and

who had an NRS score for shoulder pain at T0 of ≥1. AROM for ABD and FF showed a significant

decrease at T1, compared to T0, and did not improve substantially over time (Table 3). The changes

in AROM for ABD were larger than the changes for FF. When comparing AROM of the shoulder

between comprehensive (R(M)ND) and selective neck dissection (SND), both ABD and FF were similar

at baseline, but significant differences existed at T1 and T2, in favour of SND (Figure 1, Table 3). No

statistically significant differences in cervical mobility were found when patients who underwent SND

and R(M)ND (Figure 2 ,Table 3) were compared.

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Figure 1aAROM (°) of shoulder forward flexion before (T0) and after neck dissection at discharge (T1) and at follow-up (T2) (median and 95%CI)

150

100

500

T0 T1 T2

SNDRND/RMND

Figure 1bAROM (°) of shoulder abduction before (T0) and after neck dissection at discharge (T1) and at follow-up (T2) (median and 95%CI)

150

100

500

T0 T1 T2

SNDRND/RMND

Figure 2aCervical AROM (°) of rotation to non-operated side before (T0) and after neck dissection at discharge (T1) and at follow-up (T2) (median and 95%CI)

8060

4020

0

T0 T1 T2

SNDRND/RMND

Figure 2bCervical AROM (°) of extension before (T0) and after neck dissection at discharge (T1) and at follow-up (T2) (median and 95%CI)

6080

4020

0

T0 T1 T2

SNDRND/RMND C

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Table 3Changes (compared for each patient) of shoulder pain, shoulder and neck function after neck dissection at T1 and T2 compared to T0

Change T0-T1 95% CI of change (T0-T1)

Change T0-T2 95%CI of change (T0-T2)

SDQ* score (IQR) NA NA 18.7 (0 ; 50) (6 ; 31)

Shoulder pain present (% of cases)

55 47 ; 62 48 40 ; 56

Median NRS** for subgroup with shoulder pain (IQR)

3 (1;4) 2 ; 3 3 (2;5) 3 ; 4

Pain experienced (% of cases for subgroup with pain):

While resting 29 19 ; 39 37 26 ; 48

Lying on the shoulder

45 35 ; 55 54 41 ; 65

During movements of the shoulder

42 32 ; 53 46 33 ; 57

When walking with unsupported arm

29 19 ; 40 46 33 ; 59

Shoulder droop (% of cases)

57 48 ; 66 52 42 ; 61

AROM† decrease shoulder (compared to baseline)

Median (IQR) Median (IQR)

Abduction 34° (1 ; 102) 22 ; 66 50° (0 ; 103) 20 ; 70

Forward flexion 19° (4 ; 34) 14 ; 23 20° (0 ; 40) 10 ; 24

AROM decrease neck (compared to baseline)

Mean (SD) Mean (SD)

Rotation away from operated side

17° (15) 13 ; 19 8° (16) 5 ; 11

Extension 20° (18) 17 ; 23 15° (16) 12 ; 17

AROM differences between SND†† and R(M)ND§

T1 Difference of the median

95%CI of difference T2 Difference of the median

95%CI of difference

Abduction 93° 64 ;104 90° 60 ; 110

Forward flexion 18° 1 ; 29 20° 9 ; 37

Rotation of the neck away from operated side

7° 0 ; 12 8° 0 ; 17

* Shoulder Disability Questionnaire** Numeric Rating Scale score for pain

† Active Range of Motion†† Selective Neck Dissection§ Radical (Modified) Neck Dissection

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According to the results of the SDQ, Shoulder disability at T2 increased significantly, a median increase

of 18.7 points, from baseline (IQR 0 ; 50). Shoulder droop was present in 57 percent of cases and

remained essentially unchanged over the follow period. The percentage of patients who experienced

pain while resting, lying on the shoulder, during movements of the shoulder, and when walking with

an unsupported arm, increased between T1 and T2 (Table 3). Information on quality of life was not

available for all subjects at all time points. The number of subjects described and summary data for all

domains are presented in Figure 3.

Figure 3Boxplots showing scores for the RAND 36 domains; physical functioning (Physical), social functioning (Social), role limitations due to physical problems (Role limit Phys), role limitations due to emotional problems (Role limit emot), Emotional wellbeing (Emot Well), Energy/Fatigue (Energy Fat), bodily pain (Pain), general health perception (Health) and health change (Health Ch), on T0 (top) and T2 (bottom).

Missing data analysis

The logistic regression model indicated that no predictors significantly related to SDQ scores were

missing at T2. This indication was as expected given that the primary reasons for missing T2 scores

were unrelated to the shoulder condition of patients.

Correlations

Correlations between SDQ summary score and shoulder pain, ABD, and shoulder droop, and RAND-36

domains are listed in Table 4. Correlations with the SDQ were significant for shoulder pain, ABD,

and shoulder droop as well as for physical functioning, role limitations due to physical or emotional

problems, general mental health, vitality and bodily pain.

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Table 4Correlations (Spearman) between the SDQ score at T2 and shoulder complaints and RAND36 domains.

Correlate SDQ (T2) 95% Confidence Interval

NRS score at T2 0.70 0.53 ; 0.79

AROM abduction at T2 -0.61 -0.43 ; -0.75

Shoulder droop at T2 -0.65 -0.41 ; -0.80

RAND36 domains

Physical functioning -0.37 -0.14 ; -0.55

Social functioning -0.11 0.12 ; -0.29

Role limitations due to physical problems -0.29 -0.07 ; -0.48

Role limitations due to emotional problems -0.31 -0.11 ; -0.49

General mental health -0.23 -0.02 ; -0.42

Vitality -0.29 -0.09 ; -0.47

Bodily pain -0.53 -0.34 ; -0.68

General health perception -0.18 -0.39 ; 0.03

Health changes -0.23 -0.43 ; 0.01

Multivariate analysis

After correction for time since surgery or last radiotherapy, at dismissal from the hospital (T1) the

following variables significantly predicted SDQ scores at T2:

1. (Clustered variable) AROM of ABD and FF at T1 (with smaller AROM predicting higher SDQ scores), non-selective neck dissection and the presence of shoulder droop (both predicting higher SDQ scores) (joint influence p=0.007);

2. (Clustered variable) pain on external rotation of the shoulder (predicting higher SDQ score) and NRS score (with higher NRS scores predicting higher SDQ score) (joint influence p=0.03);

3. SDQ baseline (T0) score (p=0.04).

The remaining variables, gender, age, radiotherapy, and recruitment centre were not related to SDQ

at T2. The model R-squared was 0.50; the adjusted R-squared was 0.40.

DiscussionShoulder pain was present in 55 percent of our patients on the day of discharge from the hospital. At

follow up (T2), 48 percent reported pain. Intensity of shoulder pain was not significantly correlated

with the time passed since the operation, which is consistent with findings of van Wilgen et al. and

Chepeha et al.4,18.

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However, the NRS scores were somewhat higher at T2 than that at T1, which may be due to an

increased activity level of the patients after discharge. It is noteworthy that the number of patients

who experience pain when walking with an unsupported arm at T2 is considerably larger compared

to T1. After surgery, patients are encouraged to support their arm while walking to avoid overload of

muscles and joints of the shoulder girdle due to shoulder droop. Possibly, patients cease to support

their arm in the months after leaving the hospital. Although pain was relatively mild, it appeared to

be one of the factors related to shoulder disability. Range of motion of the neck improved over time

but did not reach baseline values within the study period. However, the decrease in cervical range of

motion for rotation at T2, compared with baseline is small; although the value statistically significant,

to the best of our knowledge, it is not clinically relevant.

AROM for ABD did not improve over the period of follow up, in either those who underwent

R(M)ND or those who underwent SND. Loss of function of the m. trapezius descendens, resulting in

a decreased AROM for ABD, is usually attributed to neuropraxia or neurolysis of the accessory nerve

as a result of the neck dissection. Indeed, van Wilgen et al. showed that a decrease in AROM for

ABD of ≥ 40° is a useful indicator for loss of function of the accessory nerve 19. AROM for ABD

was limited to a greater extent than AROM of FF, which can be explained by the fact that in ABD,

the trapezius descendens muscle is the only muscle capable of rotating the scapula laterally, whereas

during FF the serratus anterior muscle can assist in rotating the scapula laterally and the major

pectoral muscle can assist in the elevation of the arm. Post hoc stratified analysis showed that at T2,

53 percent of the patients with nerve sparing neck dissections (RMND with sparing of the accessory

nerve or SND) still had a decrease in AROM of ABD of ≥ 40°. Apparently, the duration of follow up

was too short for the nerve to recover in a substantial number of the patients. Laverick et al found that

shoulder disability improved from 6 months onwards 20. It could be argued that if shoulder disability

occurs during the period in which recovery of the accessory nerve can not yet be expected, it would

be useful to initiate rehabilitation that aims to attenuate or prevent shoulder disability, regardless of

the prognosis of trapezius dysfunction in the time thereafter.

It was decided not to exclude the 31 patients with a baseline score on the SDQ above zero, consid-

ering that they were still at risk for increasing loss of function and development of shoulder pain. As

a consequence, linear regression analyses were corrected for the SDQ baseline scores. Also, the

regression analysis was corrected for time since surgery or last radiotherapy to account for the varia-

bility of these time intervals between subjects. In total 40 percent of the variance in shoulder disability

at T2 could be explained by 2 clusters of predictors and the SDQ baseline score. Interestingly, these

clusters correspond to two clinically identifiable subgroups of patients: those with shoulder complaints

arising from the inability to stabilize the scapula adequately during movements of the arm, resulting in

a decreased active range of motion (cluster 1), and those in whom shoulder complaints are predom-

inantly related to glenohumeral joint disorders that were present at T1 (cluster 2). Although gleno-

humeral joint disorders have been described after neck dissection 7 this outcome is probably not

a direct consequence of the surgery but rather secondary to changes in postoperative use of the arm.

All of the symptoms in the two clusters (limited range of motion of ABD and FF, shoulder droop and

shoulder pain) are part of the shoulder syndrome as defined by Ewing 1. To our knowledge, it has not

been previously shown that the occurrence of this syndrome in the clinical postoperative setting is an

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actual predictor of shoulder disability four months later. Radiotherapy did not emerge as an important

predictor for shoulder disability in our study. This result is in agreement with the results of van Wilgen

et al.19. On the other hand, Taylor et al. and Chepeha et al. claimed that radiotherapy was an important

predictor for shoulder disability, although radiotherapy was not a statistically significant predictor in

the latter study 18, 21.

Objective findings of physical dysfunction correlated well with perceived shoulder disability as

measured by the SDQ, indicating that shoulder dysfunction results in performance problems in activ-

ities of daily living. Perceived shoulder disability was in turn correlated to some domains of HRQOL,

as measured by the RAND36. Bodily pain and physical functioning were the domains with the highest

correlation. Although statistically significant, these relations are not very strong (-0.53 and -0.37,

respectively). Shoulder function is just one of many factors that influence HRQOL in head and neck

cancer patients; therefore, it is not very surprising that changes in shoulder function are not reflected

dramatically in the scores of a generic quality of life instrument like the RAND36 22. Physical functioning

and bodily pain appeared to be the strongest affected domains after neck dissection.

A limitation of this study was the amount of missing data. Data of T1 were not available for some

patients because they were discharged during the weekend or without the physiotherapist being

informed. However, the impact of the missing data on the results was small, because these data were

not significantly related to the variable of interest (shoulder disability) and we were able to impute

these data. In addition, 12 patients were lost to follow up for unknown reasons. If patients dropped

out because of reasons related to their health, this may have biased the RAND36 scores. Strength

of this study was its prospective design, allowing us to investigate only those shoulder complaints

that actually arose after the neck dissection, and the combination of both objective and subjective

findings regarding shoulder function. The results of this study suggest that current management is

not sufficient to prevent shoulder disability for a substantial part of patients after neck dissection.

However, the study was not designed to evaluate the efficacy of physiotherapy after neck dissection;

consequently, no ‘control group’ is available. It is therefore difficult to judge whether the observed

shoulder disability rates occur despite physiotherapy, or as a result of insufficient physiotherapy. It is

hypothesized that more intensive physiotherapy may be required for those patients who demonstrate

all symptoms of the shoulder syndrome at dismissal from the hospital, whereas for patients in whom

only some of these symptoms are present a regimen of home-based exercises and patient education

may suffice to prevent shoulder disability. However, experimental studies are required to support or

reject this hypothesis.

Conclusion

Neck dissection due to head and neck cancer has significant negative impact on shoulder function.

Deterioration in shoulder function has a negative influence on activities of daily living. Shoulder

disability in turn decreases HRQOL. Clinical predictors for mid- to long-term shoulder disability are:

(1) a decrease in AROM of ABD and FF in combination with non-selective neck dissection and the

presence of shoulder droop, and (2) a combination of pain on external rotation of the shoulder and

higher NRS score for pain.

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AcknowledgmentProf. Dr. A.J.M. Balm for his critical comments on a previous version of this manuscript.

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REFERENCE LIST

1. Ewing M.R., Martin H. Disability following radical neck dissection; an assessment based on the postoperative evaluation of 100 patients. Cancer 1952;5:873-83.

2. Short SO, Kaplan JN, Laramore GE, et al. Shoulder pain and function after neck dissection with or without preservation of the spinal accessory nerve. Am J Surg 1984;148:478-82.

3. Carenfelt C, Eliasson K. Occurrence, duration and prognosis of unexpected accessory nerve paresis in radical neck dissection. Acta Otolaryngol 1980;90:470-3.

4. van Wilgen CP, Dijkstra PU, Nauta JM, et al. Shoulder pain and disability in daily life, following supraomohyoid neck dissection: a pilot study. J Craniomaxillofac Surg 2003;31:183-6.

5. Dijkstra PU, van Wilgen PC, Buijs RP, et al. Incidence of shoulder pain after neck dissection: a clinical explorative study for risk factors. Head Neck 2001;23:947-53.

6. Krause HR. Shoulder-arm-syndrome after radical neck dissection: its relation with the innervation of the trapezius muscle. Int J Oral Maxillofac Surg 1992;21:276-9.

7. Patten C, Hillel AD. The 11th nerve syndrome. Accessory nerve palsy or adhesive capsulitis? Arch Otolaryngol Head Neck Surg 1993;119:215-20.

8. Sist T, Miner M, Lema M. Characteristics of postradical neck pain syndrome: a report of 25 cases. J Pain Symptom Manage 1999;18:95-102.

9. Leipzig B, Suen JY, English JL, et al. Functional evaluation of the spinal accessory nerve after neck dissection. Am J Surg 1983;146:526-30.

10. Nowak P, Parzuchowski J, Jacobs JR. Effects of combined modality therapy of head and neck carcinoma on shoulder and head mobility. J Surg Oncol 1989;41:143-7.

11. Kuntz AL, Weymuller EA, Jr. Impact of neck dissection on quality of life. Laryngoscope 1999;109:1334-8.

12. McNeely ML, Parliament M, Courneya KS, et al. A pilot study of a randomized controlled trial to evaluate the effects of progressive resistance exercise training on shoulder dysfunction caused by spinal accessory neurapraxia/neurectomy in head and neck cancer survivors. Head Neck 2004;26:518-30.

13. Salerno G, Cavaliere M, Foglia A, et al. The 11th nerve syndrome in functional neck dissection. Laryngoscope 2002;112:1299-307.

14. Robbins KT, Medina JE, Wolfe GT, et al. Standardizing neck dissection terminology. Official report of the Academy’s Committee for Head and Neck Surgery and Oncology. Arch Otolaryngol Head Neck Surg 1991;117:601-5.

15. van der Heijden GJ, Leffers P, Bouter LM. Shoulder disability questionnaire design and respon-siveness of a functional status measure. J Clin Epidemiol 2000;53:29-38.

16. Hays RD, Morales LS. The RAND-36 measure of health-related quality of life. Ann Med 2001;33:350-7.

17. van Wilgen CP. (2004) Physical Therapy after Neck Dissection; a guideline for examination and treatment of shoulder complaints after neck dissection (in Dutch). Retrieved January, 2008, from http://nfhsg.vze.com.

18. Chepeha DB, Taylor RJ, Chepeha JC, et al. Functional assessment using Constant’s Shoulder Scale after modified radical and selective neck dissection. Head Neck 2002;24:432-6.

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19. van Wilgen CP, Dijkstra PU, van der Laan BF, et al. Shoulder complaints after neck dissection; is the spinal accessory nerve involved? Br J Oral Maxillofac Surg 2003;41:7-11.

20. Laverick S, Lowe D, Brown JS, et al. The impact of neck dissection on health-related quality of life. Arch Otolaryngol Head Neck Surg 2004;130:149-54.

21. Taylor RJ, Chepeha JC, Teknos TN, et al. Development and Validation of the Neck Dissection Impairment Index. Arch Otolaryngol Head Neck Surg 2002;128:44-49.

22. Streiner D.L., Norman G.R. Health measurement scales, a guide to their development and use. 3 ed. New York: Oxford University Press Inc.; 2003. p. 22-3.

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CHAPTER 7Psychometric properties of three patient reported outcome measures for the assessment of shoul-der disability after neck dissection

Martijn M. Stuiver MSc1,2, Marieke R. ten Tusscher MSc1, Anita van Opzeeland, PT3, Wim Brendeke, PT4,

Robert Lindeboom PhD2, Pieter U. Dijkstra PhD5, Neil K. Aaronson PhD 6.

1. Department of Physiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands

2. Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical

Centre, University of Amsterdam, Amsterdam, The Netherlands

3. Department of Physiotherapy, Medical Centre Leeuwarden, Leeuwarden, The Netherlands

4. Department of Physiotherapy, Rijnstate Hospital, Arnhem, The Netherlands

5. University of Groningen, University Medical Centre Groningen, Department of Rehabilitation and

Department of Oral and Maxillofacial Surgery, Groningen, the Netherlands

6. Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute,

Amsterdam, The Netherlands

Submitted

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ABSTRACTBackgroundPatient-reported outcome measures evaluating shoulder disability after neck dissection (ND) have

not been sufficiently validated. We assessed the psychometric properties of the Shoulder Disability

Questionnaire (SDQ), Neck Dissection Impairment Index (NDII) and the Shoulder Pain and Disability

Index (SPADI) in patients after ND.

Methods107 patients completed the SDQ, NDII and SPADI on 4 occasions over 6 months, and underwent

physical examination. We assessed internal consistency, test-retest reliability, clinical- and construct

validity, and responsiveness to change. The possibility of combining the NDII and SPADI items into

a single scale was explored by Rasch-analysis.

ResultsAll questionnaires exhibited good reliability and validity. We were successful in fitting a Rasch model

to the data.

ConclusionThe results support the suitability of the SDQ, NDII and the SPADI for use in ND patients. Combining

the SPADI and NDII in a single Rasch-scale improves item difficulty distribution, but reduces variability

and discriminative ability.

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IntroductionShoulder complaints such as pain and restricted range of motion are well known sequelae of neck

dissection (ND) for head and neck cancer 1. Shoulder complaints can impact negatively on daily

activities, and can compromise the patient’s health-related quality of life 2-4. The prevalence of

shoulder disability after ND ranges from 20% after selective neck dissection (SND) to 77% after radical

neck dissection (RND), although there is considerable variability across studies 1,5,6.

Patient-reported outcome measures (PROMs) are used in research and clinical practice to quantify

the subjective shoulder complaints resulting from neck dissection. A number of PROMs are currently

available to assess shoulder complaints, but their psychometric properties for use in ND populations

have been insufficiently established. This complicates the interpretation of study findings and may

also account, in part, for the variability observed in reports of the prevalence of ND-related shoulder

complaints and disability 1,7.

The University of Washington Quality of Life questionnaire (UW-QOL) 8-11, the Shoulder Disability

Questionnaire (SDQ)2,5,8,9, the Shoulder Pain and Disability Index (SPADI)12,13, and the Neck dissection

impairment index (NDII)8,9,13-16 are the most commonly used PROMs for assessing ND related shoulder

complaints 1. The UW-QOL is a head-and-neck cancer specific questionnaire that includes a single

item regarding shoulder function 17. Although this may suffice for screening purposes 8, the lack of

detail limits its usefulness in evaluating changes in shoulder complaints over time in the context of

prevention or treatment trials. The SDQ and SPADI were developed for use in patients with general

shoulder pathology 18-20. Although both questionnaires have exhibited good psychometric properties

when used in various clinical populations 21-23, neither questionnaire has been validated for use in a

ND population. The NDII was developed specifically to assess the disability and quality of life impact

of neck dissection. Preliminary data supported its validity in a single, small cross-sectional study 14.

Although the SDQ, SPADI and the NDII all assess shoulder complaints, they do so in different ways. The

SDQ reflects primarily the International Classification of Human Functioning and Health (ICF)-domain

of physical function. The SPADI also includes items related to activity restriction, although these are

limited to non-complex activities such as reaching for and carrying objects. While the SDQ and SPADI

are more comprehensive in the assessment of shoulder pain, the NDII includes assessment of more

complex activities such adverse changes in overall activity level. Additionally, it contains items relating

to the ICF-domain of social participation, such as the ability to work and to engage in social and

recreational activities.

The primary aim of our study was to conduct a comprehensive evaluation of the psychometric

properties of the SDQ, the SPADI and the NDII when used in patients who have undergone a neck

dissection (ND), including reliability, validity and responsiveness to change over time. Additionally,

we were interested in determining, with the use of item response theory analysis, the extent to

which it is empirically justifiable to combine the items of the SPADI and the NDII into a single, more

comprehensive measure of shoulder complaints, and to evaluate the psychometric properties of such

a combined measure.

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Methods Setting and patients

We recruited patients consecutively from three specialized HNC-centres in the Netherlands:

The Netherlands Cancer Institute, the Medical Centre Leeuwarden and the Rijnstate Hospital Arnhem.

Their treating physiotherapist recruited patients during regular outpatient control visits. All patients

provided written informed consent. The medical ethics committees of the participating hospitals

approved the study. Patients were eligible for the study if they had undergone a neck dissection

1 to 3 months earlier as part of their treatment for HNC and were aged 18 years or older. Exclusion

criteria included: lack of basic written and oral command of the Dutch language; serious psychiatric

or cognitive problems that would preclude completion of self-report questionnaires; prior serious

shoulder complaints unrelated to the neck dissection (e.g., due to orthopaedic or rheumatoid

disorders); or accessory nerve damage prior to the neck dissection.

Sociodemographic and medical characteristics

We collected age, gender, height and weight, primary tumour, type and extent of neck dissection,

(neo)adjuvant medical treatment (radiotherapy, chemoradiation, chemotherapy) of the neck from the

medical record. Highest level of education, current profession and leisure activities involving use of

the arm or neck on the operated side were collected through self-report.

PROMS

The SDQ is a 16 item scale with three response categories (yes/no/not applicable). Sum scores are

calculated as the percentage of applicable items that are endorsed 18. The SPADI is a 13 item scale

which uses a 0-10 numerical rating scale 20. For both the SDQ and SPADI, higher scores indicate

more complaints. The NDII contains 10 items, with 5 response options with verbal anchors ranging

from ‘not at all’ to ‘a lot’. Higher scores indicate fewer complaints 14. A Dutch translation of the

NDII was not available. Therefore, we performed a standard forward-backward translation procedure.

The provisional Dutch version of the NDII was then pilot tested in a small sample of 10 patients

to evaluate clarity. This led to minor rephrasing of three questions, after which the Dutch NDII was

considered fit for further psychometric evaluation.

The SDQ, NDII and SPADI were administered at four time points: (T1) during a follow up visit 1-3

months after surgery; (T2) within 7 days after T1; (T3) and (T4) during regular medical control visits

approximately 3 and 6 months after T1. At T3 and T4, patients were asked to indicate whether or not

they had a need for rehabilitation treatment of their shoulder.

We assessed health-related quality of life at all time points except T2 with the Dutch language version

of the RAND 36-item Health Survey (RAND-36) 24,25, a generic 36 item questionnaire that has been

used in previous studies addressing shoulder morbidity in Dutch HNC centres 2,4. The RAND-36

includes 9 scales assessing physical functioning, social functioning, role limitations due to physical

problems, role limitations due to emotional problems, mental health, vitality, bodily pain, general

health perception and health change.

Figure 1 summarizes the measurements taken at all timepoints.

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Physical examination

At all time points except for T2, we measured active range of motion (AROM) for abduction using

an inclinometer according to a standardized protocol and assessed the presence of pain (yes/no)

on passive external rotation of the shoulder. AROM for abduction is indicative of accessory nerve

dysfunction 26 and, like pain on external rotation, is a predictor for shoulder disability 2.


Statistical analyses were performed using R, version 2.15.2 (R Core Team, Vienna, Austria) 27,and OPLM

(CITO, Arnhem, the Netherlands) 28.

Figure 1Studyflow

Descriptive statistics

We generated descriptive statistics (frequency and percentage, mean and standard deviation or

median and range, as appropriate) for sociodemographic and medical variables. We calculated sum

scores for the SDQ, SPADI and NDII, and linearly transformed all scores to obtain a 0-100 score range,

maintaining the original scoring directions. For all follow up points, we calculated summary statistics

(mean, standard deviation, median, minimum and maximum) per scale, as well as floor and ceiling

effects (expressed as the proportion of patients with the worst and best possible score). We used

mean imputation for patients with less than 50% items missing on a questionnaire, and excluded

patients with more than 50% missing items.

Item Response Theory Scaling

One of the objectives of the study was to examine, by means of Item Response Theory analysis (IRT)

the possibility of combining the NDII and SPADI items into a single scale.

Rasch and related IRT based models estimate ‘item difficulty’ of individual items, together with person

(dis)ability on a common logit scale. This enables visualization of item difficulty along the continuum

of a construct to detect gaps and redundancies in difficulty of items. Also, it provides a meaningful

ordering of the items, which enhances clinical interpretation.

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Rasch models have been applied to improve questionnaires in many settings, including the assessment

of quality of life and mood in cancer survivors 29,30. Using a Rasch model has important benefits, as

it results in a scale with true metric properties. Also, the resulting scale is considered ‘person free’,

meaning that the observed measurement properties hold true for other populations as well 31. In

Rasch analysis, item fit tests can be used to evaluate the appropriateness of the item response scales,

i.e whether item score categories should be collapsed before summation. Rasch analysis assumes, and

tests, the unidimensionality of a scale. After exploratory factor analysis and inspection of the scree

plot, we performed Rasch analysis on the combined NDII and SPADI items with the OPLM software

package. We estimated item difficulty locations, assessed the extent of item difficulty coverage along

the continuum of subjective shoulder disability, and tested the fit of the combined items to the

unidimensional Rasch model.

The SDQ was not included in this analysis, since it contains a ‘not applicable’ response option that

prohibits meaningful dichotomization of responses, which is a prerequisite for Rasch analysis. Data

from all time points were used in the analysis.

Item difficulties were estimated using conditional maximum likelihood estimation in a one parameter

logistic model (Rasch). Because this method makes no assumptions on the distribution of data in

the sample or about the way the sample is selected, it accommodates the use of dependent

observations 32. The Rasch analysis consisted of two parts. First, we examined the appropriateness

of the rating scale of each item of the SPADI and NDII in OPLM and collapsed disordered rating step

categories. Second, we fitted the data to the one parameter logistic model with the collapsed rating

categories. Fit of the items to the unidimensional model was tested using specific item oriented fit

statistics, so-called M-tests, that compare deviations of observed and expected frequencies of item

scores for shoulder patients. M-tests values follow a t-distribution and values between - 2 and +2

indicate fit for an item 28. Overall fit of the combined scales to the unidimensional Rasch model was

examined using the R1c statistic P-value, that should exceed P > 0.05 to accept the model for the

data 28. We then calculated absolute agreement between expected and observed item scores, condi-

tional on the sum score. We plotted the item difficulty locations to identify gaps and redundancies

and to assess the extent to which measurement sensitivity and comprehensiveness could be improved

by combining both questionnaires.

Additionally, we evaluated the combined scale alongside the original PROMS using classical test

theory, as described below. For this purpose a sum score was calculated by summing the item scores

as used in the IRT analysis, and a linear transformation was employed to obtain a 0-100 score, with

higher scores indicating more complaints.

Reliability

We calculated intraclass correlation coefficients (ICC(2,1)) 31 for all scales, using the T1 and T2 measure-

ments to assess test-retest reliability coefficients, and Cronbach’s alpha coefficient 31 on the T1 data

to estimate internal consistency.

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Clinical validity

To assess clinical validity, we calculated the area under the curve (AUC) of the Receiver Operating

Characteristic curve (ROC-curve) for the SDQ, SPADI, NDII, and the combined scale, with the patients’

self-reported need for rehabilitation as the criterion. The AUC reflects the probability that the

questionnaires correctly classify patients as having a self-reported need for shoulder rehabilitation.

Known groups validity is also an aspect of clinical validity 31. To establish this property of each of the

scales, between group comparisons of median scores were made for several subgroups of patients

based on T1 data: patients with RND or modified RND (level 1-5 dissection) versus SND; patients

with AROM for abduction ≥90° versus <90°; and patients who had shoulder pain on external rotation

versus patients who did not. Previous research has demonstrated that shoulder disability is signifi-

cantly different between these subgroups 2,33.

Construct (Convergent and divergent) validity

We assessed convergent and divergent correlations between each questionnaire and the RAND-36

domains as well as shoulder range of motion. Also, correlations between all questionnaires were

calculated. For this purpose, we constructed univariable linear multilevel models, with random

intercepts per patient to account for the repeated measurements. All variables (SDQ, NDII, SPADI,

combined scale, ROM for shoulder abduction and scores on each of the RAND-36-domains) were

centred and scaled by subtracting the mean and dividing by the standard deviation, to obtain

Beta coefficients equal to the correlation coefficient. We expected moderate to high correlations

(r>0.40) 34 of the PROMs with AROM for shoulder abduction and the RAND-36 domains physical

functioning, role functioning-physical and bodily pain, moderate correlations (0.3< r <0.5) 34 with

social functioning, and small correlations (r<0.3) 34 with role functioning-emotional, mental health,

energy, general health perception and health change. Additionally, we generated a plot representing

the mean scores of SDQ, NDII, SPADI and the combined scale over time in relation to ROM for

shoulder abduction to visually assess responsiveness to change of the scales compared to an external

reference measure.

ResultsWe enrolled 107 patients in the study. Characteristics of the sample are shown in Table 1. Ninety-two

patients (86%) returned their T2 questionnaires. T2 questionnaires that were completed and returned

later than 8 days after T1 were excluded from the test-retest analyses (n= 32). Additionally, some

questionnaires contained too much missing data and were therefore excluded from the analysis,

leaving between 54 and 58 evaluable patients available for the T2 measurement (Table 3) . Patients

who did not return their questionnaire (in time) were, on average, 6 years younger, and 2 weeks closer

in time to post-surgery, than patients who did.

Eighty-eight patients (82%) completed the T3 questionnaires and 82 (77%) the T4 questionnaires.

Number of available questionnaires, mean time since surgery, and reasons for loss to follow-up are

depicted in Figure 1. Not all patients returned fully completed questionnaires. Missing data on the

questionnaires was < 10% at all time points, except for the SPADI at T1 (14% missing).

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Table 1Descriptive statistics of the study sample

Characteristic 1/2 Frequency PercentTotal number of participants 107 100

Male 78 73

Median age (min-max) 62 (31-83)

Median BMI (min-max) 25.6 (15.2-42.6)

Localisation primary tumour

Larynx/pharynx 7 6

Oropharynx/ tongue 43 40

Salivary glands 11 10

Skin/ lip 34 32

Other 12 12

T classification

Carcinoma in situ 1 <1

1 20 19

2 25 23

3 12 11

4 6 6

x 17 16

unknown* 26 24

N classification

0 39 36

1 20 19

2 16 15

x 6 6

unknown* 26 24

Surgical procedure

Radical (modified) neck dissection 33 31

Accessory nerve sacrificed 10 10

Sternocleidoid muscle sacrificed 40 37

Internal jugular vein sacrificed 32 30

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Characteristic 2/2 Frequency PercentRadiotherapy/chemotherapy

Neoadjuvant radiotherapy 11 10

Neoadjuvant chemoradiation 2 2

Adjuvant chemotherapy 2 2

Currently on chemotherapy 1 <1

Adjuvant radiotherapy 46 43

Currently on radiotherapy treatment 18 17

Education†

Elementary school 11 10

Secondary school (high school) 15 14

Vocational education 43 40

Higher vocational education (B) 22 21

University 13 12

Employment‡

None (retired, unemployed) 46 43

Desk job 35 32

Light physical work 8 8

Moderate to heavy physical work 6 6

Homemaker 4 4

Leisure activities involving use of arm/neck§

No relevant activities reported 37 35

Sports/ exercise 39 36

Handcrafting (timbering etc.) 17 16

Gardening 8 8

Community work 3 3

Musician 1 1

Other 2 2

* For patients who had previously been treated elsewhere, no TN classification is available† Level of education is missing for 2 persons‡ Employment is missing for 8 persons§ If participants were active in more than one category, the most strenuous activity category is reported

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Item Response Theory analysis

For the IRT analysis, only complete data from all time points were used and patients with zero-scores

on all items were excluded. Thus, a total of 292 observations were included in the analysis.

Visual inspection of the screeplot suggested unidimensionality of the combined items. Also, the first

factor explained 60% of the variance, and although the second added another 9% explained variance,

the correlation between the two factors was >0.90 at all time points. We considered this sufficient

evidence to proceed with the Rasch analysis.

Rating scale analysis showed disordered rating scale step categories for all items, which was resolved

by dichotomising the rating scales of the SPADI and the NDII. We recoded SPADI item scores <4 as

0 and scores ≥ 4 as 1. For the NDII, we recoded the categories ‘not at all’ and ‘a little’ as 0 and all

higher scores (‘moderate’ to ‘very much’) as 1. After dichotomisation, a Rasch-type model could be

fitted, with a R1c of 71.5 with 66 degrees of freedom (p=0.30), indicating good model fit. Absolute

agreement of expected and observed item scores, conditional on the sum score, ranged between

78% and 96% (median 88%). The overall ICC between expected and observed scores was 0.996.

Figure 2 displays the item difficulty spread of separate and combined SPADI and NDII items. From this

plot it is apparent that the NDII and SPADI both have gaps in item difficulty coverage, which can be

resolved by combining the two scales. There was also some overlap, with 4 items having equal item

difficulty. Table 2 shows the item content ordered by item difficulty.

Figure 2Item difficulty on a logit scale fo the Shoulder Pain and Disability Index (SPADI), the Neck Dissection Impairment Index (NDII) and the combined scale. Dots represent scale items and are stacked in case of equal item difficulty

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Table 2Item order (easy to difficult) and the problems addressed in the combined questionnaire using dichomotomized responses. The italicized items have equal difficulty

Item* Problem queried

N5 Limitations with lifting heavy objects.

S12 Difficulty with carrying heavy objects of 10 pounds (5 kg)

S11 Difficulty with placing an object on a high shelf

S1 Pain at its worst > 3 on Numeric Rating Scale

S3 Pain when reaching for something on a high shelf

N2 Bothered by stiffness in neck or shoulder

N1 Pain or discomfort of the neck or shoulder

N10 Limitations with work (including work at home)

N6 Limitations reaching up to kitchen top level

S7 Difficulty with washing the back

N9 Limitations in leisure time activities

N7 Diminished overall activity level

S2 Pain when lying on the involved side

S8 Difficulty with putting on an undershirt or jumper

S5 Pain while pushing with involved arm

S4 Pain when touching the back of the neck

S6 Difficulty with washing hair

S9 Difficulty with putting on a front buttoned shirt

N3 Difficulty with self care

S13 Difficulty with removing something from back pocket

N4 Limitations with lifting light objects

N8 Diminished participation in social activities

S10 Difficulty with putting on trousers

* Letters and numbers correspond to the original scale and item (N= Neck Dissection Impairment Index, S= Shoulder Pain and Disability Index).

Classical Test Theory analysis

Reliability, floor- and ceiling effectsAll questionnaires exhibited good to excellent internal consistency and test-retest reliability, with

Cronbach’s alpha ranging from 0.91 to 0.96 and ICC(2,1) from 0.84 to 0.93. The NDII exhibited fewest

floor effects, followed by the SPADI, SDQ and the combined scale. Floor effects increased with follow

up time and ranged up to 56% in the combined scale at T4. Some ceiling effects were present for

the SDQ and the combined scale. The number of valid questionnaires, reliability statistics, scores

summary statistics and floor/ceiling effects at all time points are shown in Table 3.

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Table 3Number of valid questionnaires, reliability and descriptive statistics for the questionnaires at all time points.

Instruments*N

valid alpha†ICC(2,1) (95%CI )‡ P Mean SD Median Min Max

Floor effect§

Ceiling effect§

SDQ T1 103 0.91 33 28.4 31 0 100 19 3

T2 58 0.84 (0.74 - 0.90)

<0.001 27 28.0 25 0 100 23 1

T3 87 27 26.2 20 0 100 25 1

T4 77 14 18.9 0 0 81 40 0

SPADI T1 92 0.96 23 21.8 17 0 80 16 0

T2 56 0.91 (0.85 ; 0.95)

<0.001 23 22.9 16 0 82 20 0

T3 85 18 18.9 12 0 77 19 0

T4 76 12 17.7 3 0 86 33 0

NDII T1 101 0.94 73 21.0 78 10 100 5 0

T2 54 0.93 (0.87 ; 0.96 )

<0.001 75 21.2 78 10 100 11 0

T3 85 80 19.1 85 8 100 13 0

T4 76 87 12.7 90 43 100 20 0

Combined scale T1 104 0.94 28 28.8 17 0 100 26 2

T2 56 0.90 (0.84 ; 0.94)

<0.001 25 29.3 9 0 91 39 0

T3 88 19 26.3 7 0 100 42 1

T4 78 11 19.6 0 0 87 56 0

*Original item scores were used for calculating sum scores of the individual instruments, and dichotomized item scores for the combined scale. Lower scores indicate less disability on the Shoulder Pain and Disability Index (SPADI), Shoulder Disability Questionnaire (SDQ) and combined score, and higher disability on the Neck Dissection Impairment Index (NDII).†Cronbach’s alpha as calculated on t1 data‡ test-retest reliability between t1 and t2§Floor- and ceiling effects are expressed as the percentage of respondents with respectively the best and worst possible score.

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Clinical validityThere were no statistically significant differences between the questionnaires in the ability to discrim-

inate between patients with or without a self-reported need for treatment. At T3 and T4, 29 and

17 patients, respectively, expressed a need for treatment,. The area under the receiver-operating

characteristic curves (AUC) was 0.85 (95%CI 0.78 – 0.94) for the SDQ, 0.85 (95%CI 0.77 – 0.94) for

the SPADI, 0.85 (0.77 – 0.94) for the NDII and 0.79 (95%CI 0.69 – 0.90) for the combined scale. At T4,

the discriminatory ability was less for all scales, with an AUC of 0.77 (95%CI 0.63 – 0.91) for the SDQ,

0.71 (95%CI 0.57 – 0.86) for the SPADI, 0.74 (95%CI 0.58 – 0.90) for the NDII and 0.72 (95%CI 0.57 –

0.87) for the combined scale.

Known groups comparisonMedian scores on the SDQ, SPADI, NDII and the combined scale differed in the expected direction

between all known groups (Table 4). All differences were statistically significant at the 0.05 level, with

the exception of the comparisons between R(M)ND and SND, where only NDII score differences were

significant .

Convergent correlations, divergent correlations and responsiveness to changeConvergent and divergent correlations with the RAND-36 domains and objectively measured shoulder

function were as expected (Table 5). Visual assessment of change in mean scores of the SDQ, NDII,

SPADI and the combined scale showed a strong association over time with change of shoulder AROM

for abduction, demonstrating their responsiveness to change (Figure 3).

Table 4Known group comparisons at T1*

Scale Type of neck dissection AROM abduction Pain at passive external rotation of the shoulder

R(M)ND SND <90° >90° yes no

33 74 Z p 68 39 Z p 22 85 Z p

SDQ† 38 28 -0.9 0.17 40 6 -5.5 <0.01 52 19 -3.3 <0.01

SPADI‡ 22 13 -1.4 0.08 22 4 -4.2 <0.01 32 13 -3.5 <0.01

NDII § 70 80 1.8 0.03 68 86 4.7 <0.01 68 80 2.5 <0.01

Combined Scale

26 13 -1.3 0.10 30 4 -4.7 <0.01 52 13 -3.6 <0.01

* Listed are number of patients per subgroup, median scores, and Z-scores and corresponding p- values from a Mann-Whitney U test with continuity correction.† Shoulder Disability Index; higher scores indicate more disability‡ Shoulder Pain and Disability Index; higher scores indicate more disability§ Neck Dissection Impairment Index; higher scores indicate less disability

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Figure 3Mean scores over time for Shoulder Disability Questionnaire (SDQ), Shoulder Pain and Disability Index (SPADI), Neck Dissection Impairment Index (NDII) and the combined scale. For ease of inter-pretation an inverse score is used for the NDII (lower score indicating less complaints), and the Y-axis for shoulder abduction is reversed (descending line for Active Range of Motion (AROM) reflects improved shoulder function). T2 data are omitted because AROM was not measured at T2.

DiscussionOur results provide support for the reliability and validity of the SDQ, SPADI and the NDII for

assessing shoulder complaints after neck dissection, with the SPADI and NDII exhibiting the highest

(and comparable) reliability. While the SPADI provides more detail on pain, the NDII would be the

obvious choice if aspects of activity and social participation are of interest. Also, the NDII was

the only scale that was sensitive to the type of neck dissection. In addition, the NDII exhibited the least

floor effects. Floor effects on all scales increased over time, as shoulder function improved in a large

number of patients. Floor effects were largest in the combined scale. Post-hoc analysis of the number

of patients with a self-expressed need for treatment among patients with a 0-score on the combined

scale, showed that this was the case for only one patient. This could indicate that the observed floor

effects appropriately reflect the absence of serious shoulder complaints.

We hypothesized that the scales could be complementary, and used Rasch analysis to explore this

possibility. In order to combine the NDII and SPADI in a Rasch model, item scores were dichotomised.

Our choice for the cut-off points of the NDII was to a certain extent arbitrary. Different cut-points

have been described for dichotomising 0-10 point numeric (pain) scales as used on the SPADI 35,36.

We also considered the often used 5-point cutoff, but that resulted in misfit of the Rasch model.

This indicates that the 4-point cutoff is the most optimal to discriminate between trait levels.

Dichotomising responses comes at the cost of losing variability in the data, but in return it improved

interpretability. The IRT-analysis showed that a number of items had disordered step-ratings which

was resolved by dichotomisation.

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From figure 2 it is apparent that patients with a disability score between -1 and 0 logit, and from 0.5 to

1.5 logit cannot be distinguished from one another with the SPADI. The same applies for patients with

NDII scores between -2 and -1 logit, and between 0 and 1 logit. Combining the SPADI and NDII into

a single scale resolved these gaps and resulted in a more even spread of item difficulties.

Some limitations of this study should be noted. Only 60 patients returned their T1 questionnaires within

an appropriate time window, which limited the number of observations available for the test-retest

analysis. Also, at all time points there was a substantial number of invalid questionnaires due to

missing or ambivalent responses (e.g., two response options chosen for a single item). Although this

was below 10% at most time points, it nevertheless suggests that a small percentage of patients found

it difficult to complete the questionnaires. The number of missing items could possibly be reduced

with computer-aided assessment, which can provide instant feedback on missed items. However,

considering that most patients in this population are over 60 years of age, one cannot assume that all

patients will have the requisite computer skills or have access to the internet. This should be less of

a problem with future generations of patients.

Although sufficient, the sample size in our study was relatively small, particularly for the IRT analysis.

Therefore, although our results are promising, they need to be confirmed in future studies.

Clinical validity was, in part, assessed using patients’ self-expressed need for shoulder rehabilitation

as a criterion. While a clinically relevant anchor, it should be pointed out that perceived need for

treatment may be influenced by other factors than shoulder complaints alone 2.

Our initial aim was to include all questionnaires that had previously been used in studies on shoulder

complaints after neck dissection, but we chose not to include the UW-QoL 17 because of its very limited

coverage of shoulder problems (a single item). The Disability of Arm Shoulder and Hand -question-

naire has also been used in a fairly recent study evaluating shoulder complaints after neck dissection 37,

but that study was published after the enrolment of the current study had started. Hence, this scale

was not included in our study. A recent cross-sectional clinimetric study provided some evidence for

the reliability and validity of the DASH in patients following neck dissection 38.

Although our study provides information on the performance of the scales between 1 and 8 months

after neck dissection, future studies are needed to evaluate the scales when used earlier or later in

the cancer care trajectory of these patients.

Notable strengths of the study include its longitudinal design, the inclusion of shoulder range of

motion measures, and the comprehensive approach taken to psychometric evaluation, in particular,

the use of item response theory.

ConclusionThe results of this study support the suitability of the SDQ, NDII and the SPADI for assessing shoulder

complaints in individual patients after neck dissection, and for evaluating change in these complaints

over time. Combining the SPADI and NDII into a single scale and dichotomising the responses yields

a Rasch-scale which allows for true metric measurement and provides a meaningful item ordering as

well as better spread of item-difficulty along the continuum of shoulder disability, but at the expense

of lower variability and discriminative ability.

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Table 5Correlation coefficients between the shoulder questionnaires and the RAND-36* domains and shoulder abduction.

Shoulder questionnaires

SDQ SPADI NDII COMBINED SCALE

Shoulder questionnaires

SDQ† 1 0.78 -0.76 0.77

SPADI‡ 1 -0.75 0.91

NDII§ 1 -0.87

Rand-36 domains

Physical functioning -0.45 -0.52 0.49 -0.54

Social functioning -0.41 -0.37 0.48 -0.44

Role functioning physical -0.49 -0.40 0.47 -0.43

Role functioning emotional -0.28 -0.23 0.31 -0.26

Menthal health -0.28 -0.24 0.28 -0.28

Vitality -0.41 -0.45 0.45 -0.47

Pain -0.59 -0.55 0.65 -0.59

Health perception -0.19 -0.19 0.24 -0.25

Health change -0.33 -0.27 0.37 -0.34

Shoulder range of motion

Abduction -0.56 -0.46 0.50 -0.49

* RAND 36-item Health Survey; higher scores indicate better health† Shoulder Disability Index; higher scores indicate more disability‡ Shoulder Pain and Disability Index; higher scores indicate more disability § Neck Dissection Impairment Index; higher scores indicate less disability

AcknowledgementWe would like to thank M.L. Vos, M.B. Pantlin and J.C. Chepeha for their assistance with the trans-

lation of the NDII, and P. Venema and E.M. de Boer for patient recruitment.

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19. Elvers RI, Oostendorp RAB, N SI. The Dutch-language version of the Shoulder Pain and Disability Index (SPADI-Dutch Version) in patients after subacromial decompression according to Neer: internal consistency and construct validity. Dutch Journal of Physical Therapy 2003;113:126–31.

20. Roach KE, Budiman-Mak E, Songsiridej N, Lertratanakul Y. Development of a shoulder pain and disability index. Arthritis Care Res 1991;4:143–9.

21. Beaton D, Richards RR. Assessing the reliability and responsiveness of 5 shoulder questionnaires. J Shoulder Elbow Surg 1998;7:565–72.

22. Bot SDM, Terwee CB, van der Windt DA, Bouter LM, Dekker J, de Vet HC. Clinimetric evalu-ation of shoulder disability questionnaires: a systematic review of the literature. Ann Rheum Dis 2004;63:335–41.

23. van der Windt DA, van der Heijden GJ, de Winter AF, Kroes BW, Deville W, Bouter LM. The responsiveness of the shoulder disability questionnaire. Ann Rheum Dis 1998;57:82-7.

24. van der Zee KI, Sanderman R, Heyink JW, de Haes H. Psychometric qualities of the rand 36-item health survey 1.0: A multidimensional measure of general health status. Int J Behav Med 1996;3:104–22.

25. van der Zee KI, Sanderman R. Het meten van de algemene gezondheidstoestand met de RAND-36, een handleiding. 2nd ed. Groningen: Research Institute SHARE, UMCG, Groningen University; 2012.

26. Dijkstra PU, van Wilgen CP, Buijs RP, Brendeke W, de Goede CJ, Kerst A, et al. Incidence of shoulder pain after neck dissection: a clinical explorative study for risk factors. Head Neck. 2001;23:947–53.

27. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing. wwwR-projectorg. 2013.

28. Glas CAW, Verhelst NDG. One Parameter Logistic Model (OPLM). Arnhem, the Netherlands; 1995.

29. Smith AB, Wright P, Selby PJ, Velikova G. A Rasch and factor analysis of the Functional Assessment of Cancer Therapy-General (FACT-G). Health Qual Life Outcomes 2007;5:19.

30. Lambert S, Pallant JF, Girgis A. Rasch analysis of the Hospital Anxiety and Depression Scale among caregivers of cancer survivors: implications for its use in psycho-oncology. Psycho-Oncology 2011;20:919–25.

31. Streiner DL, Norman GR. Health Measurement Scales. New York: Oxford University Press; 2008.

32. Verhelst NDG, Glas CAW. The one parameter logistic model. In: Fischer GH, Molenaar IW, editors. Rasch Models: foundations, recent developments and applications. New York: Springer-Verlag; 1995.

33. Cheng PT, Hao SP, Lin YH, Yeh AR. Objective comparison of shoulder dysfunction after three neck dissection techniques. Ann Otol Rhinol Laryngol. 2000;109(8 Pt 1):761–6.

34. Cohen J. Statistical power analysis for the behavioral sciencies. New Your: Academic Press;1977.

35. Fejer R, Jordan A, Hartvigsen J. Categorising the severity of neck pain: Establishment of cut-points for use in clinical and epidemiological research. Pain. 2005;119:176–82.

36. Serlin RC, Mendoza TR, Nakamura Y, Edwards KR, Cleeland CS. When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. Pain. 1995;61:277–84.

37. Carr SD, Bowyer D, Cox G. Upper limb dysfunction following selective neck dissection: A retro-spective questionnaire study. Head Neck. 2009;31(6):789–92.

38. Goldstein DP, Ringash J, Irish JC, Gilbert R, Gullane P, Brown D, et al. Assessment of the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire for use in patients following neck dissection for head and neck cancer. Head Neck. 2013. doi: 10.1002/hed.23593

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CHAPTER 8General discussion and future directives

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PreambleLymph node dissection is still a fundamental part of cancer treatment, and continues to be a source of

treatment-related morbidity. As long as this is the case, efforts should be made to minimize morbidity

by further improving surgical techniques and postoperative management, and by offering appropriate

interventions and rehabilitation, if needed.

Wound complications after inguinal lymph node dissectionOur research has shown that postoperative wound complications are still a major source of short-term

morbidity from inguinal lymph node dissection (ILND), despite efforts to optimize surgical techniques

and postoperative management of open ILND. A central aim of our research was to identify risk factors

for wound complications after ILND in patients with penile cancer, and to try to replicate the findings

of previous studies as well as explore additional risk factors in patients with melanoma. In general, we

could only partially confirm the results of previous studies. Moreover, the findings in our penile cancer

cohort were inconsistent with the findings in the melanoma cohort. None of the additional risk factors

included in our research were associated significantly with complications 1,2.

Inguinal lymph node dissection is a rather uncommon procedure, due to the low incidence of cancers

leading to inguinal lymph node metastases. As a consequence, the number of studies that have

addressed risk factors for wound complications after ILND is also limited. The observed differences

in complication rates and identified risk factors across studies may, in part, be due to variations in

research methodology, such as the definition of outcomes, or the statistical approach used. It is also

likely that the influence of many risk factors is small, and therefore difficult to detect in the relatively

small samples that have been investigated thus far. So, despite best efforts, there is still insufficient

evidence about the factors that consistently elevate the risk of surgical wound complications after

ILND.

Since complication rates of this procedure remain high, there is a clear need for further improvement

in the quality of care, as well as a need for further research in larger series of patients. We would

recommend that this procedure only be performed in high-volume medical centers, and that a multi-

center, prospective complication registry be established, based on clear and commonly agreed upon

definitions of and criteria for classifying complications.

Meanwhile, we should look for options to limit postoperative wound complications after inguinal

lymph node dissection. The effectiveness of introducing simple interventions, such as local antiseptic

treatment in the preoperative and early postoperative phase (e.g., using chlorhexidine scrubs),

could be explored. In addition, the effectiveness of fibrin sealants and collagen sponges for tissue

management could be further evaluated in this population of patients. Tissue sealing products may

reduce seroma formation by improving tissue apposition, which would reduce the need for repeated

puncture and limit skin traction. This could potentially reduce overall wound complication rates.

Minimally invasive (videoscopic) surgery for inguinal lymph node dissection may be a promising

alternative to open ILND. Results from observational studies suggest that this procedure potentially

limits morbidity, without compromising the quality of the surgery 3, but evidence from randomized

controlled trials is still needed. There is one recently registered randomized controlled trial on this

subject, which is currently ongoing 4.

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LymphoedemaLymphoedema is another major source of morbidity after lymph node dissection in several anatomical

regions. Most interventions to reduce the incidence of lymphoedema lack a solid evidence base, and

the available research suffers from serious limitations. Our systematic review of conservative (i.e., non

pharmacological and non-surgical) interventions for prevention of upper limb lymphoedema after

breast cancer treatment included 10 randomized controlled trials of several types of intervention:

manual lymph drainage alone or in combination with exercise or compression 5-8; different postoper-

ative shoulder rehabilitations protocols 9-11; and the safety of strength training 12,13. For most interven-

tions, the quality of the evidence was low, due to methodological limitations and heterogeneity of the

findings. Therefore, clinical uncertainty in this area remains.

In our own trial on prevention of lower-limb lymphoedema after inguinal lymph node dissection,

we were unable to demonstrate a statistically significant risk-reducing effect of class-II graduated

compression stockings 14. This finding should not, however, be considered as definitive proof of the

absence of any protective effect of compression stockings after inguinal lymph node dissection. Our

trial was relatively small, and the dropout rate was higher than anticipated. To our knowledge, our

is the only full-scale randomized controlled trial on the use of graduated compression stockings to

prevent lymphoedema of the lower-limbs. Additional trials are needed.

No randomized studies have yet been performed to evaluate other interventions for prevention of

lower-limb lymphoedema. The (cost-) effectiveness of possible preventive treatments, in particular

manual lymph drainage and surveillance with early intervention, needs to be investigated. Future high

quality randomized controlled trials are therefore still needed to strengthen the evidence base on the

prevention of both upper-limb and lower-limb lymphoedema after lymph node dissection in patients

with cancer.

The lack of a generally agreed upon criterion for defining clinically relevant lymphoedema is an

important limitation in the current available evidence 15, and a major obstacle to designing high quality

trials in the future. Most of the methods used for diagnosing lymphoedema in clinical trials are based on

volumetry, which has important limitations. The literature reflects a wide range of cut-off values used

for defining clinically relevant volume change from baseline or volume difference between treated and

untreated limbs 16. This suggests that these cut-offs are, to some extent, arbitrary. Changes in (limb)

volume do not necessarily imply the presence of lymphoedema. Volumetric methods are unsuitable

for assessing the presence of lymphoedema in other relevant areas of the body, such as the genital

area and abdomen after inguinal lymph node dissection, the breast or thorax after axillary lymph

node dissection, and the head and neck region after neck dissection. It should also be recognized

that lymphoedema is a condition characterized by more than change in volume, such as changes in

inflammatory state and tissue compliance. Currently, there are no valid and reliable measures for

lymphoedema that include the latter outcomes, and thus more methodological work is required.

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Shoulder morbidity after neck dissectionOur study on the incidence and impact of shoulder disability after neck dissection showed that,

overall, about half of the patients experienced shoulder pain after neck dissection. For most patients,

shoulder complaints did not recover within the study period, regardless of the type of dissection 17.

Patients with a selective neck dissection experienced less functional loss and less disability than

patients with a radical or radical modified neck dissection, even if, in the latter case, the accessory

nerve was spared. This underscores the fact that, despite preserving anatomical continuity,

the accessory nerve still suffers substantial damage if the lymph node dissection is extensive.

Therefore, whenever possible and whenever deemed oncologically safe, neck dissection should be

performed as selective as possible.

Even more conservative and less invasive neck dissection may be possible in patients with clinical

N0 neck status. In the foreseeable future, sentinel lymph node dissection (SLND) may become

a viable alternative to elective neck dissection. Evidence suggests that SLND could replace elective

neck dissection in some types of cancer 18-21. Still, while SLND has become widely accepted in

the treatment of breast cancer, controversy remains about its value in head and neck cancer, and

further development and validation of the technique in the latter group of patients is necessary.

Our results, that show that neck dissection not only results in a high incidence of shoulder pain and

disability, but also in compromised health-related quality of life (HRQoL), underscores the need

for reducing morbidity following this surgical intervention. Unfortunately, the current evidence on

the effectiveness of shoulder rehabilitation after neck dissection is also very limited. Results from

a non-randomized study suggest that physiotherapy in the postoperative phase may be helpful in

preventing shoulder disability 22. The only strong evidence for the effectiveness of physiotherapy for

shoulder disability associated with neck-dissection comes from randomized controlled intervention

trials in patients with shoulder disability 23. The exercise program as employed in these studies-

progressive resistance exercise aimed at improving scapulo-thoracic stability - may also be effective

in preventing shoulder disability after neck dissection.

Considering that not all patients experience shoulder pain and disability in the longer term, we should

select and invite patients for a preventive program based on their clinical risk profile. The results from

our cohort study could be used for this purpose. That study indicated that patients who exhibit loss of

function of the accessory nerve, who experience shoulder pain, and who exhibit scapular instability at

discharge from the hospital are at greater risk for developing shoulder disability. These patients could

therefore be eligible for early rehabilitation.

Initiating ‘preventive’ rehabilitation in this population of patients will be challenging. The burden of

adjuvant radiotherapy, the presence of psychosocial problems, limited financial resources and low

health literacy may lead to non-adherence and loss to follow-up. We need qualitative studies to better

understand the patients’ perspective after neck dissection, including their symptom burden, their

perceived need for rehabilitation, their preferences for different approaches to rehabilitation, and

perceived barriers to following (p)rehabilitation programs.

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When one evaluates the effectiveness of early shoulder rehabilitation after neck dissection in

a randomized controlled trial, incorporation of patient-reported outcomes for shoulder disability is

essential. Of the scales included in our clinimetric study, the Neck Dissection Impairment Index 24 or

the Shoulder Pain and Disability Index 25,26 appear to be best suited for this purpose.

The results of our item response theory (IRT) analysis supported the possibility of combining these

two scales to obtain a Rasch scale, which has potential advantages in terms of clinical interpretation.

However, such a combined scale also has some shortcomings, including larger floor effects and less

ability to discriminate between patients with and without (a self-reported) need for treatment, as

compared to the two original scales. Thus, although the IRT approach to assessing shoulder disability

after neck dissection is promising, it still requires further work.

The availability of IRT-based health status questionnaires, including those on assessing shoulder

disability after neck dissection, would facilitate e-health applications that are rapidly gaining in

popularity due to their potential for providing low-cost, personalized supportive care to patients

with cancer. Such e-health initiatives, and particularly those that involve a personal internet portal,

typically incorporate routine screening for symptoms and rehabilitation needs. The availability of

IRT-based measures facilitates the development of computer adaptive testing in such portals. This

makes it possible to assess a wide range of health problems in a reliable manner, while keeping patient

response burden to a minimum.

ConclusionAdvances in surgical diagnosis and treatment procedures, such as the introduction of the sentinel

node procedure, have reduced the need for lymph node dissection and thus the incidence of

treatment related morbidity in some patient groups. Nevertheless, in patients with regional lymph

node involvement, a more extensive resection of the regional lymph nodes is still an indispensable

part of treatment with curative intent. As a result, morbidity associated with lymph node dissection is

a reality for many cancer survivors. The results of the studies in this thesis can contribute to

improvement of care by broadening the evidence base regarding the incidence and risk factors of

wound complications after inguinal lymph node dissection, the prevention of lymphoedema after

inguinal and axillary lymph node dissection, and the incidence, impact and assessment of shoulder

disability after neck dissection. In addition, we have identified critical knowledge gaps and provided

suggestions for a patient-centered research agenda. C

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complications after inguinal lymphadenectomy in penile cancer: a historical cohort study and risk-factor analysis. Eur Urol 2013; 64:486–92.

2. Stuiver MM, Westerduin E, Meulen ter S, Vincent AD, Nieweg OE, Wouters MWJM. Surgical wound complications after groin dissection in melanoma patients - A historical cohort study and risk factor analysis. Eur J Surg Oncol 2014; 10.1016/j.ejso.2014.01.019.

3. Abbott AM, Grotz TE, Rueth NM, Hernandez Irizarry RC, Tuttle TM, Jakub JW. Minimally invasive inguinal lymph node dissection (MILND) for melanoma: experience from two academic centers. Ann Surg Oncol. 2013; 20:340–5.

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5. Zimmermann A, Wozniewski M, Szklarska A, Lipowicz A, Szuba A. Efficacy of manual lymphatic drainage in preventing secondary lymphedema after breast cancer surgery. Lymphology 2012; 45:103–12.

6. Castro-Sánchez AM, Moreno-Lorenzo C, Matarán-Peñarrocha GA, Aguilar-Rerrándiz ME, Almagro-Céspedes IA, Anaya-Ojeca J. Prevención del linfedema tras cirurgia de cáncer de mamma mediante ortesis elástica de contenctión y drenaje linfático manual: ensay clínico aleato-rizado. Med Clin Barc. 2011; 5:204–7.

7. Torres Lacomba M, Yuste Sánchez MJ, Zapico Goñi A, et al. Effectiveness of early physiotherapy to prevent lymphoedema after surgery for breast cancer: randomised, single blinded, clinical trial. BMJ 2010; 340:b5396.

8. De Voogdt N, Christiaens M-R, Geraerts I, 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:d5326–6.

9. Todd J, Scally A, Dodwell D, Horgan K, Topping A. A randomised controlled trial of two programmes of shoulder exercise following axillary node dissection for invasive breast cancer. Physiotherapy 2008; 94:265–73.

10. Bendz I, Fagevik Olsen M. Evaluation of immediate versus delayed shoulder exercises after breast cancer surgery including lymph node dissection-A randomised controlled trial. The Breast 2002; 11:241–8.

11. Cinar N, Seckin U, Keskin D, Bodur H, Bozkurt B, Cengiz O. The effectiveness of early rehabili-tation in patients with modified radical mastectomy. Cancer Nurs 2008; 31:160–5.

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13. Schmitz KH, Ahmed RL, Troxel AB, Cheville A, Lewis-Grant L, Smith R, et al. Weight Lifting for Women at Risk for Breast Cancer-Related Lymphedema: A Randomized Trial. JAMA 2010; 304:2699–705.

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14. Stuiver MM, de Rooij JD, Lucas C, Nieweg OE, Horenblas S, van Geel AN, 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; 46:120–31.

15. Disipio T, Rye S, Newman B, Hayes S. Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis. Lancet Oncology 2013; 14:500–15.

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17. 17. Stuiver MM, van Wilgen CP, de Boer EM, de Goede CJT, Koolstra M, van Opzeeland A, et al. Impact of shoulder complaints after neck dissection on shoulder disability and quality of life. Otolaryngol Head Neck Surg 2008; 139:32–9.

18. Govers TM, Takes RP, Karakullukcu MB, Hannink G, Merkx MAW, Janneke P.C. Grutters, et al. Oral Oncology. Oral Oncology 2013; 49:771–7.

19. Jozaghi Y, Richardson K, Anand S, Mlynarek A, Hier MP, Forest VR-I, et al. Frozen section analysis and sentinel lymph node biopsy in well differentiated thyroid cancer. J Otolaryngol Head Neck Surg 2013; 42:48. doi: 10.1186/1916-0216-42-48.

20. Fan SF, Zeng ZY, Peng HW, Guo ZM, Wang SL, Zhang Q. Sentinel lymph node biopsy versus elective neck dissection in patients with cT1-2N0 oral tongue squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2014; 117:186-90.

21. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Nieweg OE, Roses DF, et al. Final Trial Report of Sentinel-Node Biopsy versus Nodal Observation in Melanoma. N Engl J Med 2013; 370:599–609.

22. Salerno G, Cavaliere M, Foglia A, Pellicoro DP, Mottola G, Nardone M, et al. The 11th nerve syndrome in functional neck dissection. Laryngoscope 2002; 112(7 Pt 1):1299–307.

23. McNeely ML, Parliament MB, Seikaly H, Jha N, Magee DJ, Haykowsky MJ, et al. Effect of exercise on upper extremity pain and dysfunction in head and neck cancer survivors: a randomized controlled trial. Cancer 2008; 113:214–22.

24. Taylor RJ, Chepeha JC, Teknos TN, Bradford CR, Sharma PK, Terrell JE, et al. Development and validation of the neck dissection impairment index: a quality of life measure. Arch Otolaryngol Head Neck Surg 2002; 128:44–9.

25. Elvers RI, Oostendorp RAB, N SI. The Dutch-language version of the Shoulder Pain and Disability Index (SPADI-Dutch Version) in patients after subacromial decompression according to Neer: internal consistency and construct validity. Dutch Journal of Physical Therapy 2003; 113:126–31.

26. Roach KE, Budiman-Mak E, Songsiridej N, Lertratanakul Y. Development of a shoulder pain and disability index. Arthritis Care Res. 1991; 4:143–9.

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SUMMARYChapter One provides a general introduction to morbidity after lymph node dissection in cancer

patients. It describes the diversity of the observed morbidity in relation to the anatomical region of

the lymph node dissection, and provides the outline of this dissertation by identifying the knowledge

gaps that are addressed in the subsequent chapters.

The aim of Chapter two was to assess the frequency of surgical wound complications after inguinal

lymph node dissection (ILND) in patients with melanoma, and to assess the influence of potential

risk factors for these complications. A chart review was carried out of all patients on whom ILND had

been performed in the last ten years, and complications (infection, skin flap problems and seroma

formation) were counted and graded. Previous studies had been performed to identify risk factors

for surgical wound complications in melanoma patients undergoing ILND. We took this research

into account when selecting the candidate-predictors for the risk model. Additionally, we studied

procedure-specific aspects as possible risk factors. We could not confirm most of the findings of earlier

studies, and found that older age (OR 1.46, 95%CI 1.01 to 2.14) was the only siginificant predictor of

grade I or higher wound complications. The predictive ability of the model was small, even in a full

model containing all previously identified risk factors. This indicates that the influence of each of these

factors is small, and that there may be other, yet unidentified factors at play.

In Chapter three, we performed a similar study among patients treated with ILND for penile cancer.

In this study too, the overall complication rate was high, although the majority of complications were

minor. We identified body mass index (OR 1.76, 95%CI 1.04 to 2.96) transposition of the sartorius

muscle (OR 2.12, 95% IC 0.97 to 4.63) and bilateral dissection (OR 2.17, 95%CI 0.96 to 4.95) as the most

important risk factors for grade 2 or higher complications in this cohort.

In Chapter four, we report on a randomized controlled trial on the effectiveness of graduated

compression stockings for prevention of lymphoedema in the lower limb after ILND. In this trial we

compared the incidence of lymphoedema in patients who used a class-II compression stocking for

6 months to the incidence in patients who did not. Additionally, we compared surgical wound compli-

cation rates, body image and HRQoL between the groups. Although patients who used stockings had

a lower risk of developing lymphoedema, this difference was not statistically significant and smaller

than it is generally believed to be (RR 0.80, 95%CI 0.60 to 1.07). Additionally, we found no statis-

tically significant effect of stocking use on surgical wound complications, HRQoL, or Body Image.

Approximately one-third of the patients indicated that the stocking was uncomfortable to wear.

In Chapter five, we performed a systematic review of conservative interventions for prevention of clini-

cally detectable upper-limb lymphoedema after breast cancer treatment. We systematically searched

the major electronic databases of medical literature. Additionally, we reviewed the reference lists of

included trials and of relevant other reviews that were identified in the search.

We assessed the risk of bias in each of the included studies.

Outcome measures of interest included lymphoedema, infection, range of motion of the shoulder,

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pain, psychosocial morbidity, level of functioning in activities of daily life (ADL), and health related

quality of life (HRQoL). We included ten trials that compared different interventions. The overall

quality of the evidence was low due to risk of bias and inconsistency of results across trials.

Four of the included studies with a total of 385 patients studied the effectiveness of manual lymph

drainage (MLD). In two studies MLD was added to education and/or exercises. Two studies compared

MLD combined with compression or with exercise to education only. Based on these studies, no firm

conclusions can be drawn about the effectiveness of physiotherapy interventions containing MLD

for prevention of lymphoedema. Physiotherapy, consisting of manual lymph drainage combined with

exercise, resulted in better shoulder mobility in the first weeks after breast cancer surgery, compared

to exercise or education only (pooled estimate for abduction 21.8 degrees; 95%CI 13.6 to 30.1, and

forward flexion 14.4 degrees; 95%CI 7.1 to 21.8). Results on longer term effects were heterogenous.

Meta-analysis of three studies did not yield a statistically significant result for lymphoedema risk

reduction by delaying the onset of shoulder mobilising exercises for one week or longer, although two

out of three studies showed lower lymphoedema rates in the delayed group (pooled RR 0.59, 95%CI

0.33 to 1.06). Shoulder mobility may be better at short term follow-up after early start of exercises.

Meta-analysis of two trials on progressive resistance exercise therapy showed that resistance exercises

do not increase lymphoedema risk (RR 0.58, 95%CI 0.30 to 1.13), provided that symptoms are closely

monitored and adequately treated if they occur. Infection, pain, level of functioning in activities of

daily life, and HRQoL were scarcely used as outcome measures in the included trials, while psycho-

social morbidity was not included in any of the studies. Future high quality trials are needed to further

evaluate all the interventions studied in this review.

In Chapter six, we investigated the incidence of shoulder disfunction after neck dissection, its impact

on perceived disability, and its relation to quality of life. Additionally, we aimed to identify clinical

predictors for midterm shoulder disability. We found that overall, around 50% of the patients reported

shoulder pain and disability. Functional loss of the Trapezius muscle due to accessory nerve damage

was more prominent in patients with radical-, or modified radical neck dissection, regardless of

sparing of the accessory nerve in the latter procedure. Impaired shoulder function was associated

with perceived disability and with worse scores for some domains of HRQoL. We found that loss

of function of the accessory nerve, scapular instability and shoulder pain were useful predictors for

shoulder disability in the mid-long term, explaining 43% of the variance.

In Chapter seven, we assessed the psychometric properties of three commonly used scales; the

Shoulder Disability Questionnaire, the Shoulder Pain and Disability Index (SPADI) and the Neck

Dissection Impairment Index (NDII) in a population of patients after neck dissection. We used classical

test theory to investigate reliability and validity of each of the scales. The SPADI and the NDII exhibited

the highest reliability, but all scales were sufficiently reliable and valid for use in individual patients

after neck dissection. We used item response theory scaling to fit a Rasch model to the combined

items of the NDII and SPADI. This resulted in a better coverage of item difficulty along the continuum

of self reported shoulder disability, but the ability of this combined scale to discriminate between

patients with or without a self-perceived need for rehabilitation was less than that of the NDII and

the SPADI as single scales, and floor effects were larger.

Finally, in Chapter eight, the results of each of the studies are put into a clinical perspective and

recommendations for future research are made.

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SAMENVATTINGHoofdstuk 1 is een algemene introductie in de morbiditeit na lymfklierdissectie bij patiënten met

kanker. De diversiteit van de geobserveerde morbiditeit wordt geschetst in relatie tot de anatomische

regio van de lymfklierdissectie. De kennishiaten waar in dit proefschrift de aandacht op is gericht

worden geïdentificeerd en de doelstellingen van dit proefschrift worden gepresenteerd.

Hoofdstuk 2 beschrijft een historische cohort studie naar de incidentie van en risicofactoren voor

wondcomplicaties na liesklierdissectie bij patiënten met melanoom. Een statusonderzoek werd

verricht van alle patiënten die in de afgelopen 10 jaar een liesklierdissectie ondergingen. Complicaties

(seroomvorming, wondinfectie en wonddehiscentie/necrose) werden geteld en naar ernst ingedeeld.

Het aantal wondcomplicaties bleek hoog. Voor het te ontwikkelen risicomodel werden factoren

geselecteerd die in eerdere publicaties een relatie leken te hebben met wondcomplicaties na liesklier-

dissectie bij patiënten met melanoom. Aanvullend onderzochten we een aantal procedure-specifieke

aspecten als mogelijke risicofactoren. De meeste resultaten van eerder onderzoek konden niet worden

gerepliceerd. Alleen leeftijd was een risico factor voor graad I of ernstiger wondcomplicaties, met een

OR van 1.46 (95%BI 1.01 – 2.14) voor een standaarddeviatie toename in leeftijd. De voorspellende

waarde van de risicomodellen was klein, zelfs wanneer alle in eerder onderzoek gevonden factoren in

het model werden opgenomen. Dit suggereert dat de invloed van elk van deze factoren klein is, en

dat er mogelijk andere, vooralsnog onbekende factoren een rol spelen.

Hoofdstuk 3 beschrijft een vergelijkbare studie, bij patiënten die een liesklierdissectie ondergingen

vanwege een peniscarcinoom. Ook hier was het aantal wond complicaties hoog, hoewel het grootste

deel van de complicaties van lage ernst (graad I) was. In deze studie bleken body mass index (OR

1.76, 95%BI 1.04 - 2.96) transpositie van de m. sartorius (OR 2.12, 95%BI 0.97 - 4.63) en bilaterale

liesklierdissectie (OR 2.17, 95%BI 0.96 – 4.95) de belangrijkste risicofactoren voor graad 2 of ernstiger

complicaties.

Hoofdstuk 4 beschrijft een gerandomiseerde vergelijkende klinische studie naar de effectiviteit van

compressietherapie met behulp van klasse II therapeutisch elastische kousen gedurende 6 maanden,

voor preventie van lymfoedeem in de benen na liesklierdissectie. Aanvullend werden wondcompli-

caties, lichaamsbeeld en gezondheidsgerelateerde kwaliteit van leven vergeleken tussen patiënten

die een kous droegen en een controlegroep die dat niet deed. Hoewel de incidentie van lymfoedeem

lager was in de groep die een kous droeg, was dit verschil niet statistisch significant, en veel kleiner

dan algemeen wordt aangenomen (RR 0.80, 95%BI 0.60 to 1.07). We vonden ook geen statistisch

significante verschillen in de frequentie van wondcomplicaties, lichaamsbeeld of gezondheids-

gerelateerde kwaliteit van leven tussen de groepen. Ongeveer een derde van de patiënten gaf aan de

kous als niet comfortabel te ervaren.

In hoofdstuk 5 wordt een systematic review beschreven van conservatieve interventies voor preventie

van klinisch detecteerbaar lymfoedeem in de arm bij patiënten die door behandeling van borstkanker

een verhoogd lymfoedeem-risico hebben. De belangrijkste elektronische databases van medische

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literatuur werden systematisch doorzocht. Aanvullend werden de referentielijsten van gediscuteerde

studies en geïdentificeerde relevante reviews doorzocht. Het risico op systematisch vertekening

van resultaten van elke geïncludeerde studie werd beoordeeld. De uitkomstmaten voor de review

waren lymfoedeem, infectie, schouder mobiliteit, pijn, psychosociale morbiditeit, functioneren in het

dagelijks leven (ADL) en gezondheidsgerelateerde kwaliteit van leven.

Tien studies werden geïncludeerd, die verschillende interventies onderzochten. De kwaliteit van het

gevonden bewijs was in de meeste gevallen laag, door risico op vertekening van resultaten in de

studies en door inconsistente bevindingen van de studies. Vier van de geïncludeerde studies, met een

totaal van 385 patiënten, onderzocht de effectiviteit van manuele lymfedrainage (MLD) voor preventie

van lymfoedeem. In twee studies werd MLD als toegevoegde interventie toegepast, samen met

voorlichting en oefentherapie. Twee studies onderzochten MLD gecombineerd met respectievelijk

compressie (armkous) en oefeningen in vergelijking tot alleen voorlichting. Op basis van de gevonden

resultaten kunnen geen harde conclusies worden getrokken over de effectiviteit van fysiotherapie

interventies waarvan MLD onderdeel uitmaakt, voor preventie van lymfoedeem. Fysiotherapie,

bestaande uit MLD (al dan niet gecombineerd met oefeningen) had alleen in de eerste weken na

de chirurgische ingreep voor borstkanker een betere schoudermobiliteit tot gevolg, in vergelijking

tot alleen voorlichting of oefeningen zonder MLD (gepoolde effectmaat voor abductie 21.8 graden;

95%BI 13.6 tot 30.1, en anteflexie 14.4 graden; 95%BI 7.1 tot 21.8). Resultaten op de langere termijn

waren heterogeen.

Meta-analyse van drie studies liet geen beschermend effect voor het optreden van lymfoedeem

zien, van één week of langer uitgestelde oefentherapie, in vergelijking met een onmiddellijke start

(gepoolde RR 0.59, 95%BI 0.33 tot 1.06). Echter, in twee van de drie studies was de incidentie van

lymfoedeem lager in de groep met een uitgestelde start van oefentherapie. Schoudermobiliteit

herstelt waarschijnlijk wel sneller na vroege start van oefentherapie.

Meta-analyse van twee studies over progressieve weerstandstraining liet zien dat krachttraining in

deze vorm geen verhoogd risico geeft op lymfoedeem (RR 0.58, 95%BI 0.30 - 1.13), mits symptomen

zorgvuldig in de gaten worden gehouden en adequaat worden behandeld als deze zich voordoen.

Infectie, pijn, niveau van ADL functioneren en gezondheidsgerelateerde kwaliteit van leven waren in

weinig studies als uitkomstmaat gebruikt. Psychosociale morbiditeit werd in geen van de geïncludeerde

studies onderzocht. Toekomstige studies van hogere kwaliteit zijn nodig voor alle interventies zoals in

deze review zijn opgenomen.

Hoofdstuk 6 is een observationele studie naar de incidentie van schouderfunctie stoornissen, de

ernst van de daaruit volgende beperkingen en de impact op gezondheidsgerelateerde kwaliteit van

leven. Ook werd onderzocht welke factoren klinische voorspellers zijn voor functionele beperkingen

door schouderklachten na halsklierdissectie op middenlange termijn. In totaal rapporteerde de helft

van de patiënten schouderpijn en functionele beperkingen. Functieverlies van de m. trapezius als

gevolg van schade aan de n. accessorius was vooral aanwezig in patiënten met radicale en gemodifi-

ceerd radicale halsklierdissectie, ongeacht het sparen van de n. accessorius in de laatste procedure.

Afname in schouderfunctie was geassocieerd met ervaren beperkingen en met slechtere scores op

een aantal domeinen van gezondheidsgerelateerde kwaliteit van leven. Uitval van de n. accessorius, Cha

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instabiliteit van de scapula en schouderpijn waren voorspellers voor functionele beperkingen op de

middenlange termijn.

Hoofdstuk 7 is een studie naar de psychometrische eigenschappen van drie algemeen gebruikte

vragenlijsten voor het meten van ervaren schouderklachten, in een populatie van patiënten die

vanwege een tumor in het hoofd-hals gebied een halsklierdissectie hebben ondergaan. De studie

evalueerde de betrouwbaarheid en validiteit van de Shoulder Disability Questionnaire (SDQ), de

Shoulder Pain and Disability Index (SPADI) en de Neck Dissection Impairment Index (NDII), met behulp

van klassieke test theorie. De SPADI en de NDII hadden de hoogste betrouwbaarheid, maar alle

schalen waren voldoende betrouwbaar en valide voor gebruik bij individuele patiënten na halsklierd-

issectie. Met behulp van item respons theorie werden de items van de NDII en de SPADI in een Rasch

model gecombineerd. Dit resulteerde in een betere spreiding van item-moeilijkheid en een beter

meetbereik over het continuüm van zelfgerapporteerde schouder beperkingen. De gecombineerde

schaal maakte echter minder goed onderscheid tussen patiënten met of zonder behandelwens dan

de NDII en de SPADI apart, en had meer vloereffecten.

Ten slotte worden de resultaten van elk van de studies in Hoofdstuk 8 in een klinisch perspectief

geplaatst en worden aanbevelingen gedaan voor toekomstige studies.

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DANkWOORDHet in dit proefschrift samengebrachte onderzoek vormt een deel van ‘de verzamelde werken van mijn klinische nieuwsgierigheid’. Het zijn stuk voor stuk studies die zijn ingegeven door vragen en problemen waarmee mijn collegae en ik in de dagelijkse praktijk worden geconfronteerd. Studies, die ik heb kunnen uitvoeren naast mijn dagelijkse werk op de afdeling fysiotherapie van het Antoni van Leeuwenhoek, en bij de Universitaire Masterstudie Evidence Based Practice van het Academisch Medisch Centrum – Universiteit van Amsterdam. Ik had dat niet tot een goed einde kunnen brengen zonder de steun van velen.

Grote dank ben ik allereerst verschuldigd aan de patiënten die een bijdrage wilden leveren aan mijn onderzoek. Het is indrukwekkend hoe groot de bereidwilligheid was om te participeren in onderzoek, ondanks de emotionele en praktische belasting die de diagnose kanker toch al met zich meebrengt.

Prof. Dr. N.K. Aaronson, hooggeachte Promotor, beste Neil.Het is een groot voorrecht om met jou te mogen samenwerken. Je hebt mij een aantal kansen geboden waar menige beginnend onderzoeker jaloers op zou zijn. Het is vooral het daarmee impliciet uitgesproken vertrouwen, dat mij enorm heeft geholpen door te gaan op de ingeslagen weg. Ik zie ernaar uit onze samenwerking te continueren, en samen verder te bouwen aan onderzoek op het gebied van revalidatie en nazorg.

Prof. Dr. P.M.M. Bossuyt, hooggeachte Promotor, beste Patrick. Dank voor je adviezen en aanmoediging voor het verder verbeteren van mijn proefschrift. De eindsprint was stevig, maar de moeite waard. Ik zal in de toekomst meer oog houden voor de volgordelijkheid der dingen.

Dr. C. Lucas, co-promotor, beste Cees. Mijn afstudeeronderzoek voor de opleiding fysiotherapie, uitgevoerd onder jouw begeleiding, heeft me aan mijn aanstelling in het Antoni van Leeuwenhoek geholpen. Jaren later was je opnieuw mijn begeleider voor een afstudeerscriptie, ditmaal voor de Master EBP. En nu treed je als co-promotor op, bij mijn finale proeve van bekwaamheid. Dank voor al je humor en ondersteuning in de afgelopen jaren.

Dr. O.E. Nieweg, co-promotor, beste Omgo. De interventiestudie die in dit proefschrift is opgenomen is mede dankzij jouw inmenging tot een goed einde gebracht. Jij vond dat voldoende aanleiding om mij voor te stellen een proefschrift te gaan schrijven, met deze studie als startpunt. Het geheel is wel wat meer heterogeen geworden dan jij destijds voor ogen had, vermoed ik. Dank voor je enthousiasme, je zorgvuldige, positief kritische commentaren op mijn werk en de vanzelfsprekendheid waarmee je altijd beschikbaar was voor overleg.

De hooggeleerde leden van de promotiecommissie, Prof. dr. Raoul Engelbert, Prof. dr. Rob Scholten, Prof. dr. Mirjam Sprangers, Prof. dr. Emiel Rutgers, Prof. dr. Michiel van den Brekel en Prof. dr. Simon Horenblas. Bedankt voor de tijd die u genomen heeft om mijn proefschrift te lezen en hierover met mij van gedachten te wisselen tijdens de openbare verdediging.

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Beste Marieke. Jouw hulp bij het schrijven van de review was onmisbaar. Daarnaast heb je me ook veel werk uit handen genomen voor de POSEIDON studie. Bovenal ben je een geweldige collega, en ik hoop dan ook dat wij samen nog mooie projecten kunnen uitvoeren. Dank dat je mijn paranimf wilde zijn.

Beste Sander. Soms is het heel prettig om gewoon een uur vol te praten zonder dat het tot grote inzichten of een indrukwekkende productie leidt. Encyclopedische kennis kan een zware last zijn om te dragen (heb ik van horen zeggen), maar jij weet die last altijd goed te delen. Bedankt dat je als mijn paranimf wilde optreden.

Onderzoek opzetten, uitvoeren en opschrijven is teamwerk. Ik wil dan ook iedereen bedanken die heeft meegedacht en die als co-auteur heeft meegeschreven aan de in dit proefschrift opgenomen hoofdstukken. In het bijzonder wil ik daarbij noemen Prof. Dr. P.U. Dijkstra; beste Pieter, met je combinatie van kritische nuchterheid, ongeremd enthousiasme en groot relativeringsvermogen heb je mij als onderzoeker steeds tot voorbeeld gediend. Je interessante benadering van werkoverleg; kilometers fietsen in een rurale omgeving, bleek niet alleen aangenaam maar ook heel effectief.

Collegae van de afdeling fysiotherapie/ ergotherapie van het Antoni van Leeuwenhoek. Jullie bijdrage aan het slagen van deze onderneming mag niet onderschat worden. Elk van jullie heeft met regelmaat extra stappen moeten lopen, zodat ik mijn tijd in onderzoek kon steken. Een aantal mensen wil ik daarbij speciaal noemen. Ronald, dank voor je coaching, je adviezen over projectmanagement, en vooral voor de ruimte die je me steeds geeft om nieuwe wegen in te slaan. Miranda en Pauline, jullie inhoudelijke en organisatorische inbreng in de PROTECT studie was onmisbaar. Carla, jij liet je als derde auteur op de review gelden, en behoedde me voor het uitzoeken en opschrijven van nog meer details over details.

Collegae van de Universitaire Masterstudie Evidence Based Practice. De donderdagen van mijn werkweek staan altijd garant voor stimulerende discussies en de nodige humor. Het was prettig dat ik jullie af en toe kon lastig vallen met dilemma’s t.a.v. mijn onderzoek. Robert; dank voor je geweldige ondersteuning bij de IRT analyses.

En dan zijn er nog vele anderen (verpleegkundigen, verpleegkundig specialisten, fysiotherapeuten, zaalartsen en medisch specialisten) die in het AVL of in één van de andere centra hebben bijgedragen aan een goed lopende dataverzameling of recrutering van patiënten; dank daarvoor.

Promoveren is een klus die een stuk makkelijker te klaren is wanneer men zich geen zorgen hoeft te maken over schijnbaar alledaagse, maar belangrijke zaken zoals de logistiek van, en zorg voor, een gezin. Pap en mam, Michael en Henny, heel veel dank dat jullie altijd klaar staan om in te springen als dat nodig is.

Ten slotte.Masja; liefde van mijn leven, Luna en Finn. Ongetwijfeld heb ik jullie regelmatig tekort gedaan in de afgelopen jaren, maar nooit hebben jullie me het gevoel gegeven dat ik mij daarvoor moest verontschuldigen. Zonder jullie bijna vanzelfsprekend lijkende bemoediging en zonder jullie acceptatie van mijn soms nogal vernauwde belevingswereld, zou dit proefschrift hier nu niet hebben gelegen. Woorden van dank schieten hier tekort. Jullie zijn geweldig.

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PHD PORTFOLIOName: Martijn Matthias Stuiver

PhD period: January 2008-2014

Name PhD supervisors: Prof. Dr. Neil K. Aaronson, Prof. Dr. Patrick. M.M. Bossuyt

MSc education YearWorkload

(ECTS)

Epidemiology and Evidence based practice: Concepts 2006 8

Epidemiology and Evidence based practice: Designs 2006 12

Biostatistics: elementary analysis 2006 7

Health Care Policy Evaluation 2006 6

Advanced Epidemiology; Clinimetrics 2007 6

Advanced Epidemiology; Biostatistics 2007 6

Health Economics 2007 5

Systematic Reviews and Clinical Guidelines 2007 9

Capita Selecta 2007 5

Masterthesis 2007 12

Additional courses

Advanced Biostatistics (AMC graduate school) 2010 2,1

BROK (legislation and good clinical practice guidelines) AMC 2013 0.9

Oral presentations/ posters related to PhD researchImpact of shoulder complaints after neck dissection on shoulder disability and quality of life. (oral presentation) 6th International Quality of Life Workshop in Head and Neck Cancer, Liverpool, UK

2008 0.5

Wondcomplicaties na liesklierdissectie (oral presentation) Twaalfde Wound Consultant Society Congres, Utrecht, NL 2009 0.5

The efficacy of graduated compression stockings for prevention of lymphedema after inguinal lymph node dissection (poster). Annual meeting of the Society of Surgical Oncology. San Antonio, Texas, USA

2011 0.5

PROs in Oncologische Revalidatie: Het meten van schouderklachten na halsklierdissectie (oral presentation) Lustrumcongres Universitaire Master EBP, Amsterdam, NL

2012 0.5

Surgical wound complications after inguinal lymphadenectomy in penile cancer - an explorative historical cohort study for risk factors. (poster and brief oral presentation) 28th annual European Association of Urology congress. Milan, Italy

2013 0.5

Teaching & supervison Thesis supervision Master EBP (AMC-UvA) 3

Thesis supervision Master Clinical Health Sciences (UU) 1

Supervision of PhD student (A-CaRe PACES study) 2009 - 2014

Teaching Masterstudy Evidence Based Practice since 2009

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Attended workshops/ masterclasses related to PhD researchGetting published, Gordon Guyatt 2011 0.2

Effective scientific writing, James Coyne 2011 0.2

Other

Member of Scientific Advisory Board Priority Program ‘Exercise and Cancer’, German Cancer Aid 2013 1

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CURRICULUM VITAECurriculum Vitae Martijn Matthias Stuiver werd geboren te Aalsmeer op 12 januari 1973. Hij behaalde

in 1991 zijn Atheneum diploma aan het Haarlemmermeer Lyceum te Hoofddorp.

Van 1992 tot 1996 studeerde hij Fysiotherapie aan de Hogeschool van Amsterdam. Zijn afstudeerthesis

(‘met lof’), over electromyografische veranderingen na halsklierdissectie, schreef hij in opdracht van

de afdeling fysiotherapie van het Antoni van Leeuwenhoek te Amsterdam.

Na zijn afstuderen verkreeg hij een aanstelling bij de afdeling fysiotherapie van het Antoni van

Leeuwenhoek, waar hij heden nog steeds werkzaam is als fysiotherapeut en klinisch epidemioloog.

Van 1997 tot 1999 werkte hij bovendien als fysiotherapeut bij Fysiotherapeutisch Centrum Aalsmeer,

en van 2003 tot 2006 bij de unit Zorg en Welzijn van Avans+ te Breda, als ontwikkelaar en inhoudelijk

hoofddocent van de modulaire post-HBO opleiding Oncologie en Fysiotherapie.

In 2007 behaalde hij ‘cum laude’ zijn Master of Science in Evidence Based Practice aan de Faculteit

Geneeskunde (AMC) van de Universiteit van Amsterdam. Aan deze opleiding is hij sinds 2009

verbonden als Universitair Docent.

Naast zijn reguliere werkzaamheden was hij van 2003 tot 2010 voorzitter van de werkgroep fysio-

therapie van het Integraal Kanker Centrum Amsterdam en daarna algemeen bestuurslid, tot het

opheffen van de werkgroep in 2013. Van 2007 tot 2011 was hij bestuurslid van de Nederlandse

Vereniging voor Psychosociale Oncologie. Thans is hij bestuurslid van de stichting Onconet.

Martijn Stuiver woont in Aalsmeer, samen met zijn partner Masja Pantlin, dochter Luna (2002) en zoon

Finn (2004).

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LIST OF PUBLICATIONSM. M. Stuiver, J. D. de Rooij, C. Lucas PhD, O. E. Nieweg, S. Horenblas, A. N.van Geel, M. van Beurden,

N. K. Aaronson. 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 46:120-31.

Martijn M. Stuiver, Rosa S. Djajadiningrat, Niels M. Graafland, Andrew D. Vincent, Cees Lucas, Simon

Horenblas. Surgical wound complications after inguinal lymphadenectomy in penile cancer - an

explorative historical cohort study for risk factors. European Urology 2013: 486-92

Saskia F.A. Duijts, Marc van Beurden, Hester S.A. Oldenburg, Myra S. Hunter, Jacobien M. Kieffer,

Martijn M. Stuiver, Miranda A. Gerritsma, Marian B.E. Menke-Pluymers; Peter W. Plaisier, Herman

Rijna, Alexander M.F. Lopes Cardozo, Gert Jan Timmers, Suzan van der Meij, Henk van der Veen,

Nina Bijker, Louise M. de Widt-Levert, Maud M. Geenen, Gijsbert Heuff, Eric J. van Dulken, Epie

Boven, Neil K. Aaronson. Efficacy of cognitive behavioral therapy and physical exercise in alleviating

treatment-induced menopausal symptoms in patients with breast cancer: Results of a randomized

controlled multicenter trial. Journal of Clinical Oncology 2012; 30:4124-33

M.M. Stuiver, M ten Tusscher, C Idenburg, C Lucas, PMM Bossuyt: Prevention Conventional interven-

tions for preventing clinically detectable upper- limb lymphedema in patients who are at risk of devel-

oping lymphedema after breast cancer therapy [protocol] . Cochrane Database of Systematic Reviews

2012, Issue 4. Art. No.: CD009765

Chinapaw M.J., Buffart L.M., van Mechelen W., Schep G., Aaronson N.K., van Harten W.H.,

Stuiver M.M., Kersten M..J, Nollet F., Kaspers G.J., van Dulmen-den Broeder E., Huisman

J., Takken T., van Tulder M., Brug J. Alpe d’HuZes Cancer Rehabilitation (A-CaRe)

Research: Four Randomized Controlled Exercise Trials and Economic Evaluations in

Cancer Patients and Survivors. Int J Behav Med. 2011 May 10

H. van Waart, M.M. Stuiver, W.H. van Harten, G.S. Sonke, N.K. Aaronson. De PACES studie: Een

gerandomiseerde klinische trial naar de effectiviteit van beweging tijdens adjuvante chemotherapie

ter verbetering van fysieke fitheid en vermindering van vermoeidheid. Nederlands Tijdschrift voor

Oncologie, 2011; 8-2: 87-90.

E. Geleijn, C. Smeets, M. Vrijman, D. Kroon, E. Boven, M. Stuiver. CytoFys, behoud van kracht en

uithoudingsvermogen tijdens chemotherapie. Nederlands Tijdschrift voor Oncologie, 2011; 8-2: 80-6.

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van Waart H., Stuiver M.M., van Harten W.H., Sonke G.S., Aaronson N.K. Design of the

Physical exercise during Adjuvant Chemotherapy Effectiveness Study (PACES): a

randomized controlled trial to evaluate effectiveness and cost-effectiveness of

physical exercise in improving physical fitness and reducing fatigue. BMC Cancer.

2010 Dec 7;10:673

Marjolein A. van der Pol, Brigitte C.M. Gijsen, Martijn M. Stuiver,Yvette Engelen, Miranda J. Velthuis

Richtlijn oncologische revalidatie en de rol van de verpleegkundige, Oncologica 2010 (Juli).

Born T., Stuiver M.M. The Effect of a Therapeutic Exercise Program “Life In Balance” on the Quality of

Life in a Patient with Metastatic Breast Cancer: A Case Report. Rehabilitation Oncology. 2010; 28:1-4.

De Boer E.M., Brendeke W., Dijkstra P.U., de Goede C.J.T., Kerst A., Koolstra M., van Opzeeland A.,

Stuiver M.M., van Wilgen C.P., Wilschut M. Fysiotherapie na halsklierdissectie. Fysiopraxis 2006 (Juni);

32-36

Martijn M. Stuiver, Paul C. van Wilgen, Erlijn M. de Boer, Cees J.T. de Goede, Muriel Koolstra , Anita

van Opzeeland, Piet Venema, Margiet W. Sterken, Andrew Vincent and Pieter U. Dijkstra. Impact of

shoulder complaints after neck dissection on shoulder disability and quality of life Otolaryngology–

Head and Neck Surgery 2008; 139:32-39

Stuiver M.M. Fysiotherapeutische zorg na oncologische ingrepen in het hoofd-hals gebied. Oedeminus

2004; 3:10-12

Dijkstra P.U., van Wilgen C.P., Buijs R.P., Brendeke W., de Goede C.J., Kerst A., Koolstra M., Marinus

J., Schoppink E.M., Stuiver M.M., van de Velde C.F., Roodenburg J.L. Incidence of shoulder pain after

neck dissection: a clinical explorative study for risk factors.

Head and Neck 2001; 23:947-53

Contributions to books S. Adriaansz, M. Arïens, J.W. Baars, D. Bruinvels, O. Dethmers, S. Drentje, R. Dubbbelman, M. Holtkamp,

D. van Onna, Y. de Rooij, M. Stuiver, B. Toff. 107 vragen bij cytostatica. Academic Pharmaceutical

Productions bv, Utrecht 2012.

Stuiver M.M. Schouderklachten na halsklierdissectie in: Marinus J, Dijkstra PU (red) Jaarboek

Fysiotherapie-Kinesitherapie 2006, Houten, Bohn Stafleu, van Loghum p. 201-211

Kunst J. en Stuiver M.M. Een veranderd zelfbeeld in: Ben je weer beter? Praktische tips voor het

werken aan herstel van kanker. IKW Leiden, mei 2006

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Posters and conference abstractsJanne C. Mewes, Wim H. van Harten, Saskia F.A. Duijts, Hester S.S. Oldenburg, Marc van Beurden,

Martijn M. Stuiver, Myra S. Hunter, Jacobien M. Kieffer, Lotte M.G. Steuten, Neil K. Aaronson.

Cost-effectiveness of cognitive-behavioral therapy and physical exercise for alleviating treatment-in-

duced menopausal symptoms in breast cancer patients. (poster) ISPOR 18th Annual International

Meeting, May 2013, New Orleans, USA

Martijn M. Stuiver, Rosa S. Djajadiningrat, Niels M. Graafland, Andrew D. Vincent, Cees Lucas, Simon

Horenblas. Surgical wound complications after inguinal lymphadenectomy in penile cancer - an

explorative historical cohort study for risk factors. (poster and short oral) EAU, March 2013, Milan, Italy

Dijkstra P.U., van Wilgen P.C., Buijs R.P., Brendeke W., de Goede C.J., Kerst A., Koolstra M., M. J.,

Schoppink E.M., Stuiver M.M, van de Velde C.F., Roodenburg J.L. Incidence of shoulder pain after

neck dissection (abstract). Oral Oncology Vol 37, supplement I, 2001 April: S39

M. Velthuis, A. van der Pol, B Gijsen, M. Stuiver, H. Wittink Cancer rehabilitation, an evidence based

guideline for professionals in oncology and rehabilitation in the Netherlands, (abstract) WCPT

congress, June 23/24 2011, Amsterdam

Stuiver M.M., De Rooij J.D., Lucas C., Nieweg O.E., Aaronson N.K. The efficacy of graduated

compression stockings for prevention of lymphedema after inguinal lymph node dissection (poster).

Annual meeting of the Society of Surgical Oncology. March 2-5, 2011, San Antonio, Texas. USA.

Martijn M. Stuiver, Paul C. van Wilgen, Erlijn M. de Boer, Cees J.T. de Goede, Muriel Koolstra , Anita

van Opzeeland, Piet Venema, Margiet W. Sterken, Andrew Vincent and Pieter U Dijkstra. Impact of

shoulder complaints after neck dissection on shoulder disability and quality of life’ (oral abstract) 6th

International Quality of Life Workshop in Head and Neck Cancer. 2008, Liverpool, UK.

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The printing of this thesis was financially supported by

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UvA-DARE (Digital Academic Repository) Morbidity after ... · 9 may add to the risk of developing lymphoedema. When untreated, accumulation of proteins in the lymphatic fluid will