Accepted Manuscript Effectiveness of Postoperative Physical Therapy for Upper Limb Impairments Following Breast Cancer Treatment: A Systematic Review An De Groef, Marijke Van Kampen, Evi Dieltjens, Marie-Rose Christiaens, Patrick Neven, Inge Geraerts, Nele Devoogdt PII:

S0003-9993(15)00010-6

DOI:

10.1016/j.apmr.2015.01.006

Reference:

YAPMR 56082

To appear in:

ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION

Received Date: 30 July 2014 Revised Date:

17 December 2014

Accepted Date: 8 January 2015

Please cite this article as: De Groef A, Van Kampen M, Dieltjens E, Christiaens M-R, Neven P, Geraerts I, Devoogdt N, Effectiveness of Postoperative Physical Therapy for Upper Limb Impairments Following Breast Cancer Treatment: A Systematic Review, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2015), doi: 10.1016/j.apmr.2015.01.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Physical therapy following breast cancer treatment. EFFECTIVENESS OF POSTOPERATIVE PHYSICAL THERAPY FOR UPPER LIMB IMPAIRMENTS FOLLOWING BREAST CANCER TREATMENT: A SYSTEMATIC

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REVIEW An De Groef1, Marijke Van Kampen1, Evi Dieltjens1, Marie-Rose Christiaens2,3, Patrick

KU Leuven – University of Leuven, Department of Rehabilitation Science and University

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Neven2,4, Inge Geraerts1, Nele Devoogdt1

Hospitals Leuven, Department of Physical Medicine and Rehabilitation, Belgium 2

Department of Surgery, Multidisciplinary Breast Centre, University Hospitals Leuven,

Leuven, Belgium

KU Leuven – University of Leuven, Department of Surgical Oncology

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Department of Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium

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For correspondence contact:

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An De Groef, Physical Therapist, PhD Student University Hospitals Leuven Department of Physical Medicine and Rehabilitation Herestraat 49 3000 Leuven Tel.: +32 16 342171 Email: [email protected]

ACCEPTED MANUSCRIPT Acknowledgments

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We thank Nele Vervloesem for reading the text and giving language advice. This study was funded by the agency for Innovation by Science and Technology (Applied Biomedical Research) (IWT 110703).

ACCEPTED MANUSCRIPT Physical therapy following breast cancer treatment.

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EFFECTIVENESS OF POSTOPERATIVE PHYSICAL THERAPY FOR UPPER LIMB

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IMPAIRMENTS FOLLOWING BREAST CANCER TREATMENT: A SYSTEMATIC

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REVIEW

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ACCEPTED MANUSCRIPT 5

Abstract

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Objective: To systematically review the effectiveness of various postoperative physical

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therapy modalities and timing of physical therapy following treatment of breast cancer on

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pain and impaired range of motion of the upper limb. These modalities include passive

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mobilizations, manual stretching, myofascial therapy and active exercises.

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Data Sources: We searched the following databases: PubMed/MEDLINE, CINAHL,

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EMBASE, PEDro and Cochrane. Articles published until October 2012 were included.

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Study selection: Only (pseudo-) randomized controlled trials and non-randomized

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experimental trials investigating the effectiveness of passive mobilizations, manual stretching,

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myofascial therapy and/or exercise therapy and timing of physical therapy, following

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treatment for breast cancer, are reviewed. Primary outcomes are pain of the upper limb and/or

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range of motion of the shoulder. Secondary outcomes are decreased shoulder strength, arm

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lymphedema, limitations in activities of daily life, decreased quality of life and wound

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drainage volume. Physical therapy modalities had to be started in the first 6 weeks following

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surgery.

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Data extraction: Articles were selected by two independent researchers in 3 phases and

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compared for consensus. First the titles were analysed, then the selected abstracts and finally

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the full texts.

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Data synthesis: Eighteen randomized controlled trials were included in the review. Three

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studies investigated the effect of multifactorial therapy: two studies proved that the

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combination of general exercises and stretching is effective for the treatment of impaired

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range of motion; another study showed that passive mobilizations combined with massage

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had no beneficial effects on pain and impaired range of motion. Fifteen studies investigated

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the effectiveness of a single physical therapy modality. One study of poor quality found

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ACCEPTED MANUSCRIPT evidence supporting the beneficial effects of passive mobilizations. The only study

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investigating the effect of stretching did not find any beneficial effects. No studies were found

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about the effectiveness of myofascial therapy in the postoperative phase. Five studies found

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that active exercises were more effective compared to no therapy or compared to information

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on the treatment of impairments of the upper limb. Three studies supported the early start of

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exercises for recovery of shoulder range of motion, while four studies supported the delay of

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exercises to avoid prolonged wound healing.

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Conclusion: Multifactorial physical therapy (i.e. stretching and exercises) and active

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exercises were effective to treat postoperative pain and impaired range of motion following

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treatment for breast cancer. High-quality studies are necessary to prove the effectiveness of

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passive mobilizations, stretching and myofascial therapy as part of the multifactorial

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treatment. In addition, the appropriate timing and content of the exercise programs need to be

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further investigated.

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Keywords: Breast cancer, physical therapy modalities, shoulder range of motion, shoulder

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pain

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Introduction

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Breast cancer is the most common cancer in women.1 Both screening and treatment of breast

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cancer has improved significantly over the last few years, resulting in higher survival rates.1

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In order to improve quality of life of survivors many recent studies have focused on the

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complications related to breast cancer treatment.2 Among other aspects, quality of life is

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reduced by impairments of the upper limb, such as pain, impaired shoulder mobility,

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decreased strength and arm lymphedema. 3-5 In the acute treatment phase of the cancer, breast

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and axillary surgery and radiotherapy cause scar tissue formation, wound formation, fibrosis

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and shortening of soft tissues, such as the pectoral muscles.6-9 Initially, this may lead to upper

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limb impairments such as local postoperative pain and a subsequent decrease in range of

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motion (ROM).5, 6 In a further postoperative stage, adhesive capsulitis, myofascial

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dysfunctions and/or nerve dysfunctions can also cause pain and impaired shoulder mobility.7,

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9-11

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the subacromial space may lead to rotator cuff diseases, which can be painful and may limit

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upper limb movements as well.7-9 Besides pain and impaired shoulder mobility, decreased

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strength of the upper limb may be present in the short and the long term.5 These impairments

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of the upper limb may all lead to difficulties in performing activities of daily life.4, 6, 8.

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Another possible provoking factor of pain and impaired shoulder mobility may be

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lymphovascular disorders, such as axillary web syndrome and the development of

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lymphedema.7, 8, 12, 13

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In the literature, the main focus is on the prevention and treatment of breast cancer-related

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lymphedema. Approximately 20% of patients develop arm lymphedema after axillary

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dissection for breast cancer.5 Other impairments of the upper limb need to be studied as well.

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Prevalence rates of the most common impairments like pain and impaired range of motion

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Forward shoulder position, induced by the shortened pectoral muscles and narrowing of

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ACCEPTED MANUSCRIPT range between 12-51% and 1.5-50%, respectively, 3 months to 6 years after surgery.4-6

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Presence of limitations in activities of daily life is reported in 9-57% of patients, leading to a

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reduced quality of life.4 The wide range of prevalence rates can be explained by the various

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time points on the survival continuum and methods of measurement.5 Furthermore, different

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treatment modalities for breast cancer are combined. Certain treatment modalities, such as

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axillary lymph node dissection, radiotherapy on the axilla and mastectomy, increase the risk

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of impairments of the upper limb after breast cancer.14-16

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Because of the high prevalence rates, an effective evidence-based postoperative physical

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therapy program is necessary to treat postoperative pain and impaired ROM and to prevent

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other impairments of the upper limb and limitations in activities of daily life in the long term.

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In practice and in clinical trials four physical therapy modalities are used. First of all, passive

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mobilization techniques are recommended to restore joint mobility or to prevent muscular

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shortening.6, 17 Secondly, manual stretching and transverse strain is needed to prevent

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tightness of the pectoral muscles.9, 18 Thirdly, myofascial dysfunctions, often palpable as

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painful muscular trigger points, are seen in 45% of patients with breast cancer in the long

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term.10 Therefore, myofascial techniques such as myofascial release techniques and sustained

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trigger point compression could be useful.8 Fourthly, different types of exercises should be

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added.19 Active and/or active-assisted mobilization exercises are needed.17 Stretching

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exercises should be accompanied by scapulothoracic exercises since an increased posterior

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tilt, protraction and decreased lateral rotation of the scapula is often observed after breast

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cancer treatment.18, 20-22 Shortened pectoral muscles emphasize this posture.18, 20

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Strengthening exercises should also be included to restore arm strength and prevent

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difficulties in performing activities of daily life.17 When physical therapy is implemented,

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timing and intensity should be considered.17 This is because physical therapy can increase

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ACCEPTED MANUSCRIPT duration of wound drainage and cause seroma formation as well as prolonged wound

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healing.19, 23

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To our knowledge, no review has been published on the effectiveness of these four physical

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therapy modalities with a view to postoperative treatment of impairments of the upper limb

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following breast cancer treatment. Some reviewed the effectiveness of exercises only for

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treatment of upper limb dysfunctions following breast cancer treatment.17, 19 Others compared

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the effect of delayed exercising with immediate exercising on wound healing and shoulder

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ROM .23-24 or the effect of physical therapy on the treatment of lymphedema only.25

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Therefore, the aim of this systematic review was to investigate the effectiveness of four

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different physical therapy modalities (passive mobilizations, manual stretching, myofascial

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therapy and active exercises; combined or separated) on postoperative upper limb pain and

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impaired ROM following breast cancer treatment. Furthermore, recommendations will be

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made on what aspects of physical therapy should be included in the physical therapy program

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following breast cancer surgery and on the best time to start for each therapy.

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Materials and methods

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The literature search was limited to: PubMed/MEDLINE, CINAHL, EMBASE, PEDro and

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Cochrane. Articles in English, French and Dutch published until October 2012 were included.

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MeSH terms used at PubMed/MEDLINE for this search were: ‘ductal breast carcinoma’,

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‘breast neoplasms’ and ‘lymph node excision’, ‘exercise therapy’, ‘muscle stretching

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exercises’, ‘resistance training’, ‘musculoskeletal manipulations’. These terms were combined

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with the following general key words: ‘physical therapy modalities’, ‘physical treatment’,

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‘manual therapy’, ‘physiotherapy’, ‘mobilizations’, ‘combined physical therapy’, ‘exercise

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treatment’, ‘scar tissue treatment’, ‘myofascial treatment’, ‘myofascial techniques’ and

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‘fascial therapy’. In CINAHL, EMBASE, PEDro and Cochrane the following search strategy

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was used: ‘breast cancer’, ‘breast carcinoma’ or ‘lymph node’ combined with

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‘physiotherapy’, ‘physical therapy’, ‘rehabilitation’ or ‘exercise therapy’. Articles were

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selected independently by ADG and ED in 3 phases. (Figure 1). First the titles were analysed,

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then the selected abstracts and finally the full texts. When both authors did not agree, the

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article in question was discussed until a consensus was reached. The level of evidence was

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based on the method outlined by the National Health and Medical Research Council.26 Only

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randomized (Level II), pseudo-randomized controlled trials (i.e. alternate allocation or some

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other method) (Level III-1) and non-randomized experimental trials (i.e. controlled before-

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and-after or pre-test/post-test studies) (Level III-2) were included. The study population

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consisted of women who had undergone surgery for breast cancer. The physical therapy

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program had to be started within the first 6 weeks after surgery. Primary outcomes were pain

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and/or ROM of the shoulder. Trials that did not evaluate the effect of these parameters were

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excluded from the study. Secondary outcomes such as decreased strength, arm lymphedema,

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limitations in activities of daily life, quality of life, wound drainage volume, seroma formation

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ACCEPTED MANUSCRIPT or punction volume, are mentioned in Table I if they were measured in the selected studies.

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Table I lists each study with author and PEDro-score, sample characteristics, intervention,

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methods of measurement and results. The PEDro-score (Table 2) is a quality score out of 10.

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It is determined by the staff of ‘the Physiotherapy Evidence Database’ (PEDro) and can be

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found on http://www.pedro.fhs.usyd.edu.au. Reliability and validity of the PEDro quality

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score has been proven to be good.27 Articles with PEDro scores of 0 to 4 were considered low

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quality, of 5 and 6 moderate quality, of 7 and 8 good quality, and of 9 and 10 very good

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quality.27

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The studies included were divided in four categories, according to the 4 aspects of physical

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therapy following breast cancer surgery (passive mobilizations, manual stretching, myofascial

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therapy and active exercises). Studies that combined several physical therapy aspects into one

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program were categorised under ‘multifactorial therapy’. Separately, the results for the timing

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of physical therapy was presented.

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Results

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The literature search resulted in 1442 articles, of which 18 were included (Figure 1). All

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studies were RCTs. Table 1 shows information about the number of patients included, type of

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surgery and start of the physical therapy program in the column ‘Characteristics’. The

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‘Intervention’ column shows content, frequency, intensity and duration of the physical

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therapy program. The ‘Measurement’ column shows timing of follow-up, primary and

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secondary outcomes and methods of measurement. The last column gives the result of each

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outcome at different follow-up times.

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1. Multifactorial therapy

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Three RCTs, with a total of 348 patients, compared the effect of physical therapy (including

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different treatment modalities) with that of information 28, a home exercise program 29 or a

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general exercise program.30 The first study of good quality (PEDro 8) compared a weekly

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multifactorial program that started 4-6 weeks postoperatively and consisted of manual

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stretching and supervised active resistance exercises, with information.28 This 8-week

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program showed significantly greater improvements immediately after the intervention in

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forward flexion and abduction ROM and after 6 months. The intervention group in the study

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of Cinar et al. (PEDro 5) started exercises from day one after surgery.29 After removal of the

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drain they underwent 15 individual sessions of manual stretching and continued exercising.29

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The control group received a home exercise program on a leaflet, to be started after removal

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of the drain. Overall, ROM was significantly better in the group that had received stretching

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and exercises until 6 months after surgery.29 A more recent study of Pace do Amaral et al.

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(PEDro 5) evaluated the effectiveness of passive mobilizations and massage of scar tissue and

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lymphatic cords (20 min, 2/week, 8 sessions) additional to group exercises in women with

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limited shoulder movement (< 100°) on the first postoperative day compared to that of an

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ACCEPTED MANUSCRIPT exercise-only group.30 Women with ongoing limitations (i.e. ROM < 100°) after the program

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were referred to undergo individual care and were discontinued from follow-up analysis (i.e.

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18 patients (27%) from the mobilization/massage and exercises group and 11 patients (17%)

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from the exercise-only group, p=0.19). Twelve months after surgery, 13 patients (20%) in the

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mobilization/massage and exercises group and 24 patients (36%) in the exercises-only group

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had radiotherapy (p=0.04). There was no difference between groups in recovery of ROM 1

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and 6 months after surgery. Twelve months and 18 months after surgery, the control group

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showed better forward flexion and abduction ROM. However, differences were not

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significant.30

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2. Passive mobilizations

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One study (PEDro 6) with 257 patients investigated the effect of passive mobilizations after

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breast cancer treatment, comparing four groups: no physical therapy (1), mobilizations of the

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shoulder (2), massage of the arm (3) or both mobilizations and massage (4).31 All

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interventions started the first day after surgery and lasted for 7 days. After discharge, patients

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went to a physical therapist of their own choice. Analysis after 7 days showed that the ROM

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was greater in the group that had massage and mobilizations in comparison with that of the

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two other groups who had received massage only or no physical therapy at all. After 3

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months, there were no differences between the groups. At long-term follow-up (8-24 months),

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significantly more locoregional pain was noted in the two groups without mobilizations

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compared to the groups with mobilizations.31

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3. Stretching

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Only one RCT (PEDro 8), with a total of 61 women, studied the added value of a pectoral

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stretching program to exercises given on a pamphlet.32 The stretching program consisted of

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low-load, prolonged, passive stretches of the pectoral muscles guided by a physical therapist.

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ACCEPTED MANUSCRIPT No differences in pain and ROM were observed between groups after radiotherapy and 7

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months later.32

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4. Exercise therapy

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Five RCTs, with a total of 439 women, compared the effectiveness of an exercise program

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with that of another exercise program 33, no exercises 34 or information about exercises35-37 on

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postoperative upper limb pain and impaired ROM.

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4.1 Comparison of two exercise programs

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The intervention group in the study of de Rezende et al. (PEDro 3) followed a regimen of

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directed exercises.33 The control group was given free exercises to the biomechanical

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physiological movements of the shoulder without a strict regimen as to sequence or number of

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repetitions. The intervention showed better results for ROM, both on the 28th day and on the

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42th day.33

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4.2 Exercise therapy versus no therapy

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The intervention group in the study of Wingate et al. (PEDro 6) received active exercises,

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postural exercises, progressively resistive exercises and proprioceptive neuromuscular

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facilitation for 30 minutes twice a day during hospital stay.34 After discharge, patients had to

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follow an 8-weeks home program. The control group did not receive any treatment. Five days

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after surgery, ROM was significantly different between the two groups, in favour of the

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intervention group. Three months after surgery, this trend continued.34

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4.3 Exercise therapy versus information

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Beurskens et al. (PEDro 7) performed an RCT in which the intervention group started a

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physiotherapy program in a private practice of their own choice 2 weeks after surgery.35 This

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ACCEPTED MANUSCRIPT program consisted of strength, coordination, posture and arm/shoulder exercises, exercises to

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prevent lymphedema and advice on home exercises. Additional soft tissue massage of the

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surgical scar was given. The control group only received information on a leaflet about

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exercises during the first weeks after surgery. Three months after surgery, shoulder pain and

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ROM were significantly better in the exercise group.35 Another RCT (PEDro 4) investigated

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the effectiveness of an exercise program and education about lymphedema.36 The control

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group only received information about exercises. Abduction had improved more in the

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treatment group after 5 days and 3 months and this difference was maintained after 24

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months.36 Xie et al. (PEDro 4) randomized postoperative breast cancer survivors in an

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intervention group who performed supervised upper limb exercises and yoga or a control

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group who received information to perform the same program by themselves.37 The training

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started after the 28th day or the first cycle of adjuvant chemotherapy and lasted until

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completion of six cycles. Significantly more patients in the group with supervised exercises

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and yoga showed complete recovery of abduction ROM.37

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5. Myofascial Therapy

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To date, no RCT has reported on the effectiveness of myofascial therapy starting within the

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first 6 weeks after surgery for breast cancer.

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6. Timing of physical therapy

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Eight RCTs with a total of 1284 patients examined the timing of exercises after breast cancer

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treatment. 38-45 No studies examined the timing of the other physical therapy modalities.

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Five studies of low to moderate quality (Table 2) compared results between exercises started

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on the first postoperative day or 7 days later.38-42 In only one of these studies did the early

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group show better forward flexion ROM 2 weeks after surgery. However, one month after

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surgery, no difference was observed.38 The other authors did not find any advantages in early

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ACCEPTED MANUSCRIPT mobilizations for ROM.39-42 Significantly less drainage volume in the delayed group was

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found in one out of five studies.42 A lower incidence of seroma formation in the delayed

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exercise group was also found in two out of five studies.38,39

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In the study of Bendz et al. (PEDro 5) one group started exercising on the first day post-

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operatively and the other group 14 days after surgery.43 Flexion and abduction ROM were

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significantly better in the first group until two years after surgery. No differences were found

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for pain.43 Chen et al. (PEDro 4) investigated three different timings of a program including

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pendulum, wall climbing and pulley exercises.44 One group started exercising on the third day

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postoperatively, the second group 6 days postoperatively and the last group started after

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catheter withdrawal. There were no differences in ROM between the groups 6 months after

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surgery. Only the amount of wound drainage fluid was less in the group that had started after

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catheter withdrawal than that in the early group, starting 3 days after surgery and that in the

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delayed group, starting 6 days after.44

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In the study of Lauridsen et al. (PEDro 7) patients received a team-instructed exercise

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program.45 The program consisted of strength training, active stretching, vein pump exercises

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and extension-relaxation exercises. One group started 6 to 8 weeks after surgery and the other

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group 26 weeks postoperatively. The first group had a significantly better Constant Shoulder

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Score at 6 and 26 weeks after the intervention. The Constant Shoulder Score assesses

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subjective ROM, objective ROM and shoulder strength. At 56 weeks of follow-up, both

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groups had finished their program and no differences were found between groups.45

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Discussion

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This manuscript reviews the effectiveness of postoperative physical therapy modalities for the

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treatment of pain of the upper limb and impaired ROM of the shoulder following breast

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cancer treatment. These modalities include passive mobilizations, manual stretching,

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myofascial therapy and active exercises. Evidence concerning best timing of physical therapy

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is also reviewed.

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All studies (N=18) meeting the inclusion criteria were RCTs (Level II). Five studies were of

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high quality, 6 studies of moderate quality and 7 studies of low quality. PEDro did not score

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one study for randomization because allocation to groups was according to even or uneven

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day of birth. Randomization was concealed in only 5 studies. Patients and therapists were

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never blinded to the type of treatment. Assessors were blinded in 9 studies. Intention-to-treat

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analysis was used in 5 studies. Power calculation was performed in 7 studies.

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Two studies confirmed that multifactorial therapy consisting of manual stretching and active

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exercises is an effective method for postoperative treatment of impaired shoulder ROM

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following breast cancer treatment. 28,29 However, in both studies, the follow-up period was

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only 6 months. 28,29 Another study did not find any advantages of a multifactorial program

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compared to group exercises.30 They investigated the treatment effect of passive mobilizations

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and massage, in patients with axillary dissection and with shoulder limitations on the first

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postoperative day. The lack of a positive effect is probably related to the fact that seven

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physiotherapists performed the treatments. Physical therapists were trained before the start of

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the treatment. However, information about the standardization or criteria for the application of

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the techniques is missing. Twelve months and 18 months after surgery the exercise-only

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group showed better forward flexion and abduction ROM than the group with

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mobilizations/massage and exercises. This result is not expected since a higher rate of patients

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ACCEPTED MANUSCRIPT in the control group received radiotherapy, which is a risk factor for the development of

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impairments of the upper limb.14 A possible explanation is that they did not apply an

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intention-to-treat analysis and 24% of the patients with limited shoulder ROM were

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discontinued from follow-up analysis.

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One study reported beneficial effects of passive mobilizations on shoulder pain and ROM.

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According to PEDro, this study was of moderate quality (PEDro 6). However, it is difficult to

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assess its quality since little information is given about the method of measurement.31 The

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outcome ‘pain’ was measured by a questionnaire, of which information about the content and

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validation is missing. Follow-up measurements were performed by self-report questionnaires

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and medical file search. Long-term follow-up timing ranged from 8 to 24 months.31

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The only study investigating a pectoral stretching program did not find any added value.32 A

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possible explanation is the fact that a large number of patients did not undergo an axillary

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dissection (60%) and/or a mastectomy (79%) and none of the patients received radiotherapy

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of the thorax/axilla. These are all factors that decrease the risk of developing impairments of

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the upper limb.14, 46, 47

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No studies were found about the effect of myofascial therapy, started in the postoperative

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phase after breast cancer treatment.

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Five studies investigated the effectiveness of exercise therapy.33-37 They all found a beneficial

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effect on shoulder ROM with one 35 showing a positive effect on pain as well. The review

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article of McNeely et al. confirmed these results. They concluded as well that exercises in the

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postoperative phase are beneficial for recovery of ROM in the short term.17 The better results

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in the intervention group of Xie et al. indicate the importance of guided exercises versus a

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program autonomously performed by patients .37 However, patient characteristics were poorly

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described in this study. Hence it is not clear which type of axillary surgery (sentinel node

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biopsy or axillary dissection) patients received.37 All studies about the effectiveness of

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exercise therapy are very different in content and duration. The exercise programs consisted

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of different types of exercises: active mobilization exercises 33-35, 37, strength exercises 34, 35, 37,

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exercises to prevent lymphedema 35, postural exercises 35, coordination exercises 35 and yoga

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37

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sessions over 3 months 35 to 14 sessions over 42 days.33 Other studies did not specify the

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content 36 or duration 36, 37 of their exercise program. Three studies only had a follow-up

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period of 42 days 33, 3 months 34 or 6 months 35, allowing only short-term conclusions. As

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confirmed by McNeely et al, it seems that any exercise program is better than no therapy at

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all, but definite conclusions about which exercises, intensity and duration remain difficult to

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draw.17 In the literature, a minimal change of 13 mm on the Visual Analogue Scale is

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considered to be clinically relevant.48 In the study of Beurskens et al.35 the exercise group had

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significantly better scores on the Visual Analogue Scale after 3 months (Table I). The

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difference between groups was greater than 13 mm, indicating this result is clinically relevant

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as well. For shoulder ROM the minimal clinical relevant change varies between 15° and 24°

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in different studies.49-50 Considering this, in certain studies the better results on shoulder ROM

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in the groups receiving exercise therapy combined with stretching 29, mobilizations 31, and

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exercise therapy alone 33-35 are clinically relevant as well.

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Timing of exercise therapy was investigated by 8 RCTs.38-45 In 2 studies an early start of the

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exercises on the first day following surgery seemed more beneficial for recovery of ROM as

331

compared to a late start.38, 43 Similarly, Lauridsen et al. showed that a start within the first

332

weeks after surgery led to a faster recovery than a start 26 weeks following surgery.45

333

However, patients in the delayed group caught up and fully recovered after finishing their

334

exercise therapy program.45 On the contrary, different studies showed that incidence of

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seroma formation and wound drainage volume was higher in the group with an early start

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. Duration of the exercise programs varied between 2 sessions a day until discharge 34, 9

16

ACCEPTED MANUSCRIPT compared to the group starting more than 7 days after surgery.38, 39, 42,44 To improve wound

337

healing, patients with axillary dissection have to start mobilizing exercises at 7 to 10 days

338

post-surgery. This is confirmed by McNeely et al.,17 Chan et al.19 and Shamley et al.23 The

339

quality of these studies needs discussion. In the study of Chen et al. the time interval between

340

the early and delayed group was rather short (i.e. between 3 and 6 days post-surgery).44

341

Therefore, a significant effect on ROM may not be detectable. The content of the exercise

342

programs varied among studies which makes it difficult to compare results.33-37 Furthermore,

343

measurement methods were not always well documented 38, 39, 41 and one study had a follow-

344

up period up to only one month.38

345

Based on these results, we recommend starting a low-intensity physical therapy program in

346

order to avoid seroma formation and increased wound drainage volume.23,24, 38, 39, 42, 44 In the

347

first few days, this program should only include active mobilizing and pumping exercises of

348

the wrist and elbow.23 At 7 to 10 days post-surgery, when the wound has healed properly, the

349

intensity of the physical therapy program can be increased gradually.23 The program should

350

consist of passive mobilizations31 and the combination of manual stretching and active

351

exercises.28-29 Based on the current studies no recommendations can be made on the timing,

352

content and intensity of the exercises. No evidence is provided either for separate physical

353

therapy modalities such as stretching or transverse strain of the pectoral muscles, massage of

354

the scar(s) and myofascial release techniques. The Clinical Practice Guidelines of Harris et al.

355

recommend as well an early post-operative start of passive and active mobilizations combined

356

with stretching exercises and scar tissue massage to enhance shoulder ROM in women after

357

axillary lymph node dissection.51-52 However, the remark should be made that these

358

recommendations are not based on (pseudo-) randomized controlled trials.

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359 360

Despite the beneficial effect of physical therapy, many patients still have impairments of the 17

ACCEPTED MANUSCRIPT upper limb and limitations in activities of daily life at short and long term.5 To create a more

362

effective physical therapy program more high-quality studies should be developed. First of

363

all, breast cancer treatment has an influence on the muscles and soft tissues of the shoulder

364

girdle and trunk.8 Therefore, the effectiveness of stretching, transverse strain and myofascial

365

therapy should be further explored. Secondly, protraction of the shoulders and scapular

366

dyskinesia are provocative factors for upper limb impairments.9, 18, 22 The additional value of

367

postural exercises, core stability exercises and/or scapulothoracic exercises should be further

368

investigated. Finally, the intensity and duration of mobilizing and strengthening exercises and

369

the value of exercises guided by a physical therapist (versus non-guided exercises) should be

370

further explored. Recovery of impairments of the upper limb should be monitored by

371

objective clinical measurements. Because of the long-lasting effect of radiotherapy and/or

372

chemotherapy on soft tissues 8, patients need to be followed until 6 months after ending

373

radiotherapy and/or chemotherapy. Even after this time, patients can develop impairments of

374

the upper limb and subsequent difficulties in performing activities of daily life.5 Health care

375

providers should be aware of this and refer patients to a specialized physical therapist if

376

indicated.

377

Study limitations

378

Comparison of the studies was often complicated by a number of factors. First, several

379

treatment modalities for breast cancer were used. Certain types of surgery (axillary lymph

380

node dissection and mastectomy) and radiotherapy at the axilla may increase the risk of the

381

development of impairments of the upper limb after breast cancer.14-16 Furthermore, the extent

382

of surgery and the possible combination with other adjuvant treatment modalities such as

383

chemotherapy may influence the duration of wound healing and seroma formation.5, 6 Second,

384

different starting points and follow-up time frames were used in the included studies. Third,

385

several methods of measurement were used. A standardized way of measuring impairments of

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18

ACCEPTED MANUSCRIPT the upper limb is needed to enable more adequate comparisons. Finally, heterogeneity in the

387

physical therapy interventions applied in the different studies makes it difficult to compare

388

studies. Another limitation of this review is the low scores on the PEDro scale of an important

389

number of studies.

390

Conclusions

391

In conclusion, passive mobilizations, exercises and the combination of manual stretching and

392

general exercises are effective for improvement of shoulder ROM after breast cancer

393

surgery.28,29,31,33-37 Exercises are also effective for treatment of postoperative pain of the upper

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limb.35 Three studies supported the early start of exercises for recovery of shoulder

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ROM38,43,45, while four studies supported the delay of exercises to avoid prolonged wound

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healing.38,39,42,44

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ACCEPTED MANUSCRIPT References

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35. Beurskens CH, van Uden CJ, Strobbe LJ, Oostendorp RA, Wobbes T. The efficacy of physiotherapy upon shoulder function following axillary dissection in breast cancer, a randomized controlled study. BMC cancer 2007;7:166. 36. Box RC, Reul-Hirche HM, Bullock-Saxton JE, Furnival CM. Shoulder movement after breast cancer surgery: results of a randomized controlled study of postoperative physiotherapy. Breast cancer Res Treat 2002;75(1):35-50. 37. Xie X, Liu Z, Qu S, Guo F, Zheng Z, Liu Y et al. 169 patients with postoperative breast cancer on exercising the function of limbs and investigating quality of life: a clinical study. Chin -Ger J Clin Oncol 2010;9(10):590-3. 38. Abe M, Iwase T, Takeuchi T, Murai H, Miura S. A randomized controlled trial on the prevention of seroma after partial or total mastectomy and axillary lymph node dissection. Breast cancer 1998;5(1):67-9. 39. Schultz I, Barholm M, Grondal S. Delayed shoulder exercises in reducing seroma frequency after modified radical mastectomy: a prospective randomized study. Ann Surg Oncol 1997;4(4):293-7. 40. van der Horst CM, Kenter JA, de Jong MT, Keeman JN. Shoulder function following early mobilization of the shoulder after mastectomy and axillary dissection. Neth J Surg 1985;37(4):105-8. 41. Jansen RF, van Geel AN, de Groot HG, Rottier AB, Olthuis GA, van Putten WL. Immediate versus delayed shoulder exercises after axillary lymph node dissection. Am J Surg 1990;160(5):481-4. 42. Todd J, Scally A, Dodwell D, Horgan K, Topping A. A randomized controlled trial of two programs of shoulder exercise following axillary node dissection for invasive breast cancer. Physiotherapy 2008;94(4):265-73. 43. Bendz I, Fagevik Olsen M. Evaluation of immediate versus delayed shoulder exercises after breast cancer surgery including lumph node dissection - A randomized controlled trial. The breast 2002;11:241-8. 44. Chen SC, Chen MF. Timing of shoulder exercise after modified radical mastectomy: a prospective study. Changgeng yi xue za zhi 1999;22(1):37-43. 45. Lauridsen MC, Christiansen P, Hessov I. The effect of physiotherapy on shoulder function in patients surgically treated for breast cancer: a randomized study. Acta Oncol 2005;44(5):449-57. 46. Gosselink R, Rouffaer L, Vanhelden P, Piot W, Troosters T, Christiaens MR. Recovery of upper limb function after axillary dissection. Journal Surg Oncol 2003;83(4):204-11. 47. Liu CQ, Guo Y, Shi JY, Sheng Y. Late morbidity associated with a tumour-negative sentinel lymph node biopsy in primary breast cancer patients: a systematic review. Eur J Cancer 2009;45(9):1560-8. 48. Gallagher EJ, Liebman M, Bijur PE. Prospective validation of clinically important changes in pain severity measured on a visual analog scal. Ann Emerg Med 2001;38(6):633-8 49. Mullaney MJ, McHugh, MP, Johnson CP, Tyler TF. Reliability of shoulder range of motion comparing a goniometer to a digital level. Physiother Theory Pract 2010;26(5):32733. 50. Muir SW, Corea CL, Beaupre L. Evaluating change in clinical status: reliability and measures of agreement for the assessment of glenohumeral range of motion. N Am J Sports Phys Ther 2010;5(3):98-110. 51. Harris SR, Hugi MR, Olivotto IA, Niesen-Vertommen SL, Dingee CK, Eddy F, Allan SJ, Haylock BJ, Kwan WBC. Upper extremity rehabilitation in women with breast cancer after axillary dissection: clinical practive guidelines. Crit rev phys rehabil med 2001;13(23):91-103.

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Figure 1: Overview of the systematic review

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ACCEPTED MANUSCRIPT Table 1: Overview of the included randomised controlled trials with sample characteristics, description of the intervention, measurement and results. Author

Characteristics

Intervention

Measurement

Results

Multifactorial therapy N=160

Exercise + stretching group (N=81):

Pre-intervention, post-

ROM: post-intervention: forward flexion: +20° exercise + stretching group vs. + 13° control group

al., 2012 28

women after

supervised exercise sessions of

intervention and 6M after

(p=0.01);

PEDro: 8

ALND (N=96) or

resistance training and passive

intervention

abduction: +19° exercise + stretching group vs. +14° control group (p=0.05); external rotation and

SNB (N=64);

stretching + home program; 1x/week; 8

ROM: inclinometer

horizontal extension increased equally in both groups (p>0.05)

4-6W postop

weeks

Strength: Hand Held

ROM: 6M: abduction: +20° exercise + stretching group vs. +10° control group (p0.05)

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Kilbreath et

circumferential differences

Strength: post-intervention: abduction: +26N exercise + stretching group vs. +16N control group (p=0.04)

ADL function: EORTC

Strength: 6M: both groups increased equally (p>0.05) Arm lymphedema: prevalence: no difference between groups (p>0.05) ADL Function: no differences between groups (p>0.05)

N=57

Exercise + stretching group (N=27):

Preop, D5, 1M, 3M, 6M postop

ROM: D5: forward flexion: 133° exercise + stretching group vs. 107° control group (p0.05)

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Passive mobilizations

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Pace do

Le Vu et al.,

N=257

All patients: 5 sessions, 7D

D7, 3M, 8M-24M postop

Pain or sensitivity problems: 3M: 74% no PT group vs. 70% mobilization group vs. 72% massage group

1997 31

Women after

No PT group (N=63)

Pain or sensitivity problems:

vs. 68% mobilization and massage group (p>0.05)

PEDro: 6

ALND;

Mobilization group (N=65)

questionnaire

Locoregional pain: 8-24M: 5% mobilization groups vs. 13% no mobilization groups (p=0.03)

1D postop

Massage group (N=65)

ROM: goniometry

Mobilizations and massage group

Punction volume

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ROM: 7D: forward flexion: 143° massage and mobilization group vs. 128° massage group vs. 130° no PT

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(N=64)

group (p0.05); abduction: 124° stretch group vs. 125° control group (p>0.05)

pectoral stretching program with

Strength: digital dynamometer

Strength: no differences between groups at any point in time (p>0.05)

weights, 1x/week, 6 weeks

Arm lymphedema: prevalence,

Arm lymphedema: 7M: no differences between groups at any point in time (p>0.05)

ACCEPTED MANUSCRIPT Control group (N=30): /

circumferential differences

QOL: no differences between groups at any point in time (p>0.05)

QOL: EORTC, QLQ-C30

RI PT

Comparison of two exercise programs N=60

All patients: abduction, forward flexion,

Preop, 14D, 28D, 42D postop

ROM: 28D: forward flexion: 144° directed exercises vs. 132° free exercises (p=0.04); Abduction: 122°

et al., 2006

women after

extension and rotations exercises,

ROM: goniometry

directed exercises vs. 108° free exercises (p=0.03)

33

MRM or

40min, 3x/week, 42 days

Arm lymphedema: circumference

ROM: 42D: forward flexion: 155° directed exercises vs. 142° free exercises (p0.05); external rotation: 89°

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early group vs. 89° delayed group vs. 88° late group (p>0.05) ROM: 6M: forward flexion: 175° early group vs. 174° delayed group vs. 172° late group (p>0.05); abduction: 176° early group vs. 172° delayed group vs. 171° late group (p>0.05); external rotation: 89° early group vs. 89° delayed group vs. 88° late group (p>0.05) Wound drainage volume: axilla: 458 ml late group vs. 568 ml early group and 559 delayed group (p0.05) Punction Volume: no significant difference between groups (p>0.05)

Lauridsen et

N=139

All patients: treatment of the ward from

Preop, 6W, 12W, 26W and 56W

ADL function:

al., 2005 45

women after

day 1 + team-instructed PT including

post-intervention

6W: significantly better Constant Shoulder Score (p