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Immediate versus delayed reconstruction following surgery

for breast cancer (Review)

DSouza N, Darmanin G, Fedorowicz Z

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published inThe Cochrane Library

2011, Issue 7

http://www.thecochranelibrary.com

Immediate versus delayed reconstruction following surgery for breast cancer (Review)

Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/

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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

10DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

25INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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[Intervention Review]

Immediate versus delayed reconstruction following surgeryfor breast cancer

Nigel DSouza1, Geraldine Darmanin2, Zbys Fedorowicz3

1Oxford Deanery, Heatherwood and Wexham Park Hospitals NHS Trust, Slough, UK. 2 London Deanery, Kings College Healthcare

Trust, London, UK. 3 UKCC (Bahrain Branch), Ministry of Health, Bahrain, Awali, Bahrain

Contact address: Nigel DSouza, Oxford Deanery, Heatherwood and Wexham Park Hospitals NHS Trust, Wexham Park Hospital,

Slough, Berkshire, SL2 4HL, [email protected].

Editorial group:Cochrane Breast Cancer Group.

Publication status and date:Edited (no change to conclusions), published in Issue 9, 2011.

Review content assessed as up-to-date: 25 August 2010.

Citation: DSouza N, Darmanin G, Fedorowicz Z. Immediate versus delayed reconstruction following surgery for breast cancer.

Cochrane Database of Systematic Reviews2011, Issue 7. Art. No.: CD008674. DOI: 10.1002/14651858.CD008674.pub2.


A B S T R A C T

Background

Breast cancer is the most prevalent cancer in women and has a lifetime incidence of one in nine in the UK. Curative treatment requires

surgery, and may involve adjuvant and neo-adjuvant therapy. In many women, post-mastectomy breast reconstruction is essential to

restore body image andimprove quality of life. Timing of reconstruction maybe immediate or delayed following mastectomy. Outcomes

such as psychosocial morbidity, aesthetics and complications rates may differ between the two approaches.

Objectives

To assess the effects of immediate versus delayed reconstruction following surgery for breast cancer.

Search methods

We searched the Cochrane Breast Cancer Groups Specialised Register on 22 July 2010, MEDLINE from July 2008 to 26 August 2010,

EMBASE from 2008 to 26 August 2010 and the WHO International Clinical Trials Registry Platform (ICTRP) on 26 August 2010.

Selection criteria

Randomised controlled trials (RCTs) comparing immediate breast reconstruction versus delayed or no reconstruction in women of any

age and stage of breast cancer. We considered any recognised methods of reconstruction to one or both breasts undertaken at the same

time as mastectomy or at any time following mastectomy.

Data collection and analysis

Two review authors independently screened papers, extracted trial details and assessed the risk of bias in the one eligible study.

Main results

We included only one RCT that involved 64 women. We judged this study as being at high risk of bias. Post-operative morbidity and

mortality were not addressed, and secondary outcomes of patient cosmetic evaluations and psychosocial well-being post-reconstruction

were inadequately reported. Based on limited data there was some, albeit unreliable, evidence that immediate reconstruction compared

with delayed or no reconstruction, reduced psychiatric morbidity reported three months post-operatively.

1Immediate versus delayed reconstruction following surgery for breast cancer (Review)

mailto:[email protected]:[email protected]

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Authors conclusions

The current level of evidence for the effectiveness of immediate versus delayed reconstruction following surgery for breast cancer was

based on a single RCT with methodological flaws and a high risk of bias, which does not allow confident decision-making about

choice between these surgical options. Until high quality evidence is available, clinicians may wish to consider the recommendations

of relevant guidelines and protocols. Although the limitations and ethical constraints of conducting RCTs in this field are recognised,

adequately powered controlled trials with a focus on clinical and psychological outcomes are still required. Given the paucity of RCTsin this subject, in future versions of this review we will look at study designs other than RCTs specifically good quality cohort and case-

control studies.

P L A I N L A N G U A G E S U M M A R Y

Immediate versus delayed reconstruction following surgery for breast cancer

Curative treatment of breast cancer requires surgery, which can involve a mastectomy to remove the entire breast. Breast reconstruction

following mastectomy can be carried out either immediately or as a delayed procedure. Immediate reconstruction is carried out at the

same time as surgery while delayed reconstruction may be performedat any time following mastectomy. Several non-randomised studies

have reported differences in the psychological benefits, aesthetics and complication rates based on the timing of reconstruction. Thisreview sought to compare the effects of the timing of reconstruction on morbidity and mortality, patient satisfaction and psychosocial

well-being. Only one eligible randomised controlled trial (RCT) was found, which involved 64 women. However, because a substantial

number of participants in the study chose not to undergo delayed reconstruction, it was not possible to make a fair comparison of

the mixed group with those participants who underwent immediate reconstruction. Methodological flaws and a high risk of bias also

diminished the quality of evidence found in the RCT. Since we have only identified one RCT in this area, an updated version of this

review will evaluate other study designs specifically good quality cohort and case-control studies. Further research should aim to provide

reliable evidence for people to make informed decisions as to the best and most appropriate timing of breast reconstruction following

surgery for breast cancer.

B A C K G R O U N D

Description of the condition

Breast cancer is a malignant growth of cells originating in breast

tissue. It can spread to other parts of the body by growing into

adjacent tissues, or by breaking off and spreading via the blood-

stream or lymphatic system to seed into a distant organ or tissue,

where it may then begin to grow (metastatic spread). Metastatic

spread mayoccur in other organs, such as the liver, lung, brain and

bones. Data gathered by the International Agency for Researchon Cancer confirm that breast cancer is one of the most common

cancers in women, with 1.38 million new cases diagnosed in 2008.

Countries in the developed world have the highest age-standard-

ised incidence of breast cancer, which in Western Europe is 89.7

per 100,000 women and 76.7 per 100,000 in North America. Al-

though the incidence is lower in Eastern Europe, South America,

and Western Asia, it is still the most common cancer of women

in these geographic regions. In most of Africa, with the possible

exception of Southern Africa (41/100,000), the incidence rates are

generally lower, ranging from 19.3 per100,000 women in Eastern

Africa to 21 per 100,000 in Central Africa (GLOBOCAN 2008).

The lifetime risk in the UK for a woman to develop breast cancer

is one in nine. Over 81% of breast cancer occurs in women over

the age of 50, with the highest risk group category being 50 to 69

years (Office for National Statistics 2009).

The most common complaint is a breast lump. Other signs or

symptoms include skin abnormalities such as tethering (as if the

skin is being pulledfrom theinside), ulceration or local discoloura-

tion (peau dorange); nipple changes which may include bleed-

ing, inversion or discharge; lumps in the axilla (underarm) or un-

commonly, breast pain. Diagnosis is made by triple assessment:

clinical examination, radiological assessment which may include

mammography or ultrasound, and histopathological assessment

of cytology or biopsy. Early breast cancer is often asymptomatic

and only detected by screening with mammography.

The current five-year relative survival for localised breast cancer

(cancer which has not spread to lymph nodes or sites outside the



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breast) is 98%. If there has been regional spread by direct invasion

toadjacentlocalstructures or nearbylymph nodes,survivalis 84%.

Distant metastatic spread is considered incurable and treatment

is directed at improving life expectancy, palliating symptoms and

improving quality of life. The most common sites of spread are

bone, lung and liver, with an overall five-year survival rate of 23%for metastatic breast cancer (Jemal 2009). Life expectancy in these

cases is related to the extent of metastasis, size of tumour, lymph

node involvement and whether major organs are affected.

Treatment options for breast cancer are based on tumour type,

size, stage, grade, patient genetic predisposition, patient hormone

receptor status andpatient preferences, whichmust all be evaluated

when choosing the optimum treatment i.e. curative or palliative.

Treatment with curative intent requires surgery, with or without

radiotherapy and systemic therapy. Surgery and radiotherapy both

treat cancer at a specific, local site of disease, with surgery still

the primary method for removing cancer. Surgical treatment is

directed at the breast and may also include the axilla. Although

breast-conserving surgical (BCS) procedures (lumpectomy, quad-rantectomy and segmental mastectomy) tend to be the preferred

first option, mastectomy may be necessary if the cancer is greater

than 4 cm, multi-focal, centrally situated or of a particular in-

vasive carcinoma subtype. BCS is the surgical removal of the tu-

mour and a rim of healthy tissue surrounding the tumour, while

mastectomy involves removal of the breast, with or without skin.

Both BCS and mastectomy may vary in the extent of surgical

resection. Subcutaneous mastectomy removes breast tissue under

the skin, while radical mastectomy can remove the entire breast

with underlying pectoralis muscle. Radical mastectomy is rarely

performed in current practice due to the extensive morbidity it

causes. Axillary surgery (removal of associated lymph glands from

under the arm) is performed by sentinel lymph node biopsy, axil-lary lymph node biopsy or dissection of many lymph nodes. Sen-

tinel lymph node biopsy involves injecting radioisotope dye into

the breast tissue around the nipple, and removing the nodes to

which the dye spreads. These nodes are taken intra-operatively for

microscopic examination by histopathologists. If they are clear, no

further lymph nodes need to be removed. If the lymph nodes do

show signs of cancer, additional lymph nodes need to be removed.

The alternative approach is to proceed with the removal of many

lymph nodes based on the stage (spread) and grade of the cancer,

alongside imaging results and clinical examination findings.

Treatment with radiotherapy may be given in addition to BCS

to decrease the incidence of local cancer recurrence (the cancer

returning in the same breast), and may also target the axilla inpatients with positive lymph nodes detected by sentinel biopsy

or axillary sampling. With certain subtypes of cancer (e.g. ductal

carcinoma in situ (DCIS)), radiotherapy may not be indicated.

Systemic therapy aims to treat the whole body, not just the lo-

cal site of disease, using chemotherapy, hormone treatment or

immunotherapy. Hormones such as oestrogen and progesterone

can affect the growth of certain types of breast cancer. Selectively

blocking oestrogen action or production can shrink large cancers,

decreasing the chances of local recurrence and the likelihood of

metastatic spread. There are three types of hormone therapy; ta-

moxifen,aromatase inhibitors and pituitary suppressors. Tamox-

ifen directly blocks the effect of oestrogen on tissue. Aromatase

inhibitors e.g. anastrozole, block oestrogen production from theadrenal glands in post-menopausal women. Pituitary suppressants

e.g. goserelin, block the hormone pathways that lead to oestrogen

production. An immunotherapeutic agent, herceptin, can reduce

the chance of recurrence and disease progression in women who

carry the HER2-positive receptor. In some countries, prophylactic

bilateral mastectomies are offered to women who have inherited

BRCA gene mutations that predispose them to breast cancer.

Neoadjuvant therapy may be given before surgery in an attempt

to shrink tumours pre-operatively, and adjuvant therapy is often

given after surgeryto reducethe chanceof recurrence, and this may

include chemotherapy, hormone therapy or targeted biological

therapy.

Description of the intervention

Breast reconstruction is essential for many women to restore body

image and improve quality of life post-mastectomy. Treatment

aims to manage the psychological impact of breast cancer and in-

cludes breast reconstruction and psychological support. Recon-

struction consists of therebuilding of a womans breastusing either

tissue from other parts of the body or implantable devices such as

silicone or saline implants. This often includes the reformation of

a natural looking areola and nipple.

A range of surgical options for reconstruction are available.

Autologous tissue procedures

Autologous reconstruction uses a patients own tissue to replace

lost breast tissue. This may be carried out as an immediate recon-

struction, in the same operation as mastectomy once it is com-

pleted. Itmay also be carried outas a delayed reconstruction proce-

dure, which occurs any time after the initial operation but usually

after two months to allow skin to heal. Autologous reconstruction

may be contraindicated in cases such as previous major surgery

in the required tissue, systemic medical conditions such as hyper-

tension, chronic obstructive pulmonary disease, diabetes, patients

who smoke or who have too high or too low a body mass index

(BMI).

1. Latissimus dorsi myocutaneous flap: skin and muscle flaps

can be used to cover areas of excised tissue. This is achieved by

cutting a skin island and pivoting it under the axilla whilst

retaining the same blood supply. The flap can be used to cover an

implant, or on its own in small-breasted women.

2. Transverse rectus abdominus myocutaneous (TRAM) flaps:

these are harvested and transferred from the abdomen to the

chest wall by joining the blood vessels of the flap (the pedicle) to



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the internal mammary vessels in the chest. Blood supply to

TRAM flaps is variable. Pedicled TRAM flaps require the entire

rectus abdominus while microvascular TRAM flaps require a

(much) smaller proportion of muscle.

3. Deep inferior epigastric perforator (DIEP) flaps: these are

created from the lower abdomen without removal of muscle.Their use is limited by anatomical constraints that cannot be

predicted pre-operatively.

4. Gluteal artery perforator (GAP) flaps: these flaps include

the skin and subcutaneous tissue based on the inferior and

superior gluteal vessels where the gluteal muscle is not removed.

This procedure is generally considered a second-line option.

Tissue expanders and implantable devices

Implantable devices such as silicone or saline implants can be used

immediately if there is sufficient skin or soft tissue coverage pro-

vided by a skin flap. However, if there is insufficient tissue to cover

the implant, reconstruction can be delayed while a tissue expanderis used. Tissue expanders are placed under the pectoralis muscle

and can be inflated and later replaced with a definitive implant.

Ports located in the expanders allow them to be filled with saline

in the post-operative period. Expansion causes gradual stretching

and growth of the soft tissue such that the excess skin can then be

used at that site to cover an implant.

How the intervention might work

The timing and decision of when to carry out breast reconstruc-

tion remains controversial and will often depend on individual

circumstances, in addition to whether adjunctive radiotherapy isrequired. In planning reconstruction it is important that the pri-

mary focus should be effective cancer treatment, around which

the aesthetic goals of reconstruction must be tailored.

Immediate reconstruction

This is performed at the time of the mastectomy and is indicated

primarily for patients who are unlikely to require additional ra-

diotherapy. Predicting whether radiotherapy will be required after

surgery is not always feasible and in borderline cases may result in

a surgeon advocating delayed reconstruction.

A number of studies have shown that reconstruction is onco-

logically safe directly after mastectomy even in advanced disease,

thereby making this procedure even more acceptable for patients

(Giacalone 2010;Langstein 2003;Newman 1999). It is claimed

that early reconstruction tends to lead to betteraesthetic outcomes

(McCarthy 2005) since the breast envelope is preserved together

with the inframammary fold and offers a better prospect of recre-

ating a natural shape, with more symmetry to the breast. Adding

a myocutaneous flap (well-vascularised and non-radiated) at the

time of mastectomy can also be advantageous as it can promote

tissue healing (Bostwick 1990).

Immediate reconstruction followingbreast cancersurgery is recog-

nised to be an important consideration in the reduction of anx-

iety levels as well as in improving self-esteem and quality of life(Drucker-Zertuche 2007). One study reported that 95% of the

patients who had received immediate reconstruction were content

with the outcome as compared with 76% of those who underwent

delayed reconstruction and who also indicated that they would

have preferred immediate reconstruction (Al-Ghazal 2000).

Controversy remains over the possible detrimental effects of adju-

vant radiotherapy on immediate breast reconstruction. A number

of studies have shown that radiation after immediate reconstruc-

tion gives poor results and compromises aesthetic results. When

breasts that have been reconstructed with implants are subjected

to radiotherapy, complications may arise and these can include

impaired skin healing, fibrosis, implant extrusion and capsular

contractures (Behranwala 2006,Forman 1998;Kronowitz 2009;Tallet 2003;Whitfield 2009). Complications can also occur when

autologous flaps undergo radiotherapy. Early complications in-

clude thrombosis, flap necrosis or loss, and local wound-healing

problems, while late complications included hyperpigmentation,

fat necrosis, volume loss, and flap contracture (Kronowitz 2009;

Kronowitz 2004;Rogers 2002;Spear 2005;Thomson 2008;Tran

2001). Tissue expansion is often poorly tolerated by many pa-

tients (Tallet 2003) and can lead to complications such as a con-

cave deformity of thechest wall (Fodor 1989). Several studies have

reported contradictory results which suggest that careful choice

of immediate reconstruction technique or adjuvant therapy can

minimise some of the adverse events that can occur after adjuvant

therapy (Hussien 2004;von Smitten 1992;Williams 1995).

Delayed reconstruction

Delayed reconstruction is indicated when post-mastectomy radio-

therapy is required, or likely to be required. A further indication

would be when patients are not ready or willing to engage in plan-

ning a reconstructive procedure until more time has passed since

their diagnosis. The delayed approach is also used in partial breast

mastectomy, when the margins of resection are not known at the

time of the operation and further excision may be required. De-

layed reconstruction can be technically challenging because radi-

ation can lead to tissue fibrosis in the chest wall tissue.

Implants may be placed at the time of mastectomy, as part of a

delayed procedure, before irradiation, after which autologous flaps

are created. However, this may also result in sub-optimal outcomes

with worse cosmetic results, more painful expansion and greater

risk of revision surgery (Cordeiro 2004;Krueger 2001).

Patients who select the delayed approach have more time to con-

sider the various surgical options. A patient has to cope with the

burden of the diagnosis and the ongoing psychological pressures



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of dealing with the physical and social consequences of the disease.

Delayed reconstruction gives her the time to seekadvice from plas-

tic and breast surgeons, thereby allowing more time for evaluation

of the various reconstructive techniques available once definitive

cancer treatment has been completed. In patients who have un-

dergone radiation therapy, it also permits clinical assessment of theirradiated tissue and complications of radiotherapy such as non-

viable tissues which can be removed during reconstruction.

The disadvantages of a delayed approach are largely psychological,

due to the burden of patients living with breast deformity until

reconstruction is completed. Some studies have reported this as

leading to lower self-esteem and body image, causing depression

and anxiety (Fernandez-Delgado 2008). There are also technical

difficulties with a delayed approach, beyondthe difficulties of deal-

ing with irradiated tissue. Larger flaps are required because of the

need for skin replacement, symmetry is difficult to achieve, and

contralateral mastopexy (lifting breast tissue and removing skin)

maybe required in many cases. However, some studies have shown

that delayed procedures have had excellent long-term aesthetic re-sults (Schuster 1992). Patientsare often counselledto have realistic

expectations for the aesthetic outcome of delayed reconstruction,

especially if the field was previously irradiated. Patient evaluation

of aesthetic outcomes can vary depending on the time reconstruc-

tion takes place.

Why it is important to do this review

Outcomes such as morbidity, cosmetic outcomes and psycholog-

ical benefits may differ between immediate or delayed breast re-

construction post-mastectomy. A summary of the evidence for the

benefits, both clinical and psychological, could help facilitate bet-ter shared decision-making between clinicians and patients on the

best treatment.

O B J E C T I V E S

To assess the effects of immediate versus delayed reconstruction

following surgery for breast cancer.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised controlled clinical trials (RCTs).

Types of participants

Women in any age group with any stage of breast cancer in either

of the following two treatment groups.

1. Delayed breast reconstruction to one or both breasts post-

mastectomy.

2. Immediate reconstruction to one or both breasts concurrentwith mastectomy.

The only included trial evaluated both treatments.

Types of interventions

We compared immediate reconstruction versus delayed recon-

struction. We considered any appropriate and recognised meth-

ods of reconstruction. We included studies in which immediate

reconstruction was compared with the option of delayed or no

treatment. SeeDifferences between protocol and review

Types of outcome measures

Primary outcomes

1. Post-operative morbidity (number of surgical

complications) and mortality.

Secondary outcomes

1. Patient cosmetic or functional satisfaction with

reconstruction, assessed using any validated generic or disease-

specific questionnaire.

2. Psychosocial well-being post-reconstruction, assessed using

any validated generic or disease-specific scale.

Search methods for identification of studies

See: Breast Cancer Groupmethods used in reviews.

Electronic searches

For the identification of studies we searched the following

databases.

(1) Cochrane Breast Cancer Group Specialised Register

Details of search strategies used by the Groupfor the identification

of studies and the procedure used to code references are outlined

in the groups module (Cochrane Breast Cancer Group 2009). We

extracted trials coded with the key words surgery, carcinoma in

situ, early breast cancer, locally advanced breast cancer and ad-

vanced breast cancer for consideration. We conducted the search

on 22 July 2010.


http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/BREASTCA/frame.htmlhttp://www.mrw.interscience.wiley.com/cochrane/clabout/articles/BREASTCA/frame.htmlhttp://www.mrw.interscience.wiley.com/cochrane/clabout/articles/BREASTCA/frame.htmlhttp://www.mrw.interscience.wiley.com/cochrane/clabout/articles/BREASTCA/frame.htmlhttp://www.mrw.interscience.wiley.com/cochrane/clabout/articles/BREASTCA/frame.html

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(2) MEDLINE (via OVID) from July 2008 onwards

We ran the subject search with the Cochrane Highly Sensitive

Search Strategy (CHSS)for identifying randomised trials in MED-

LINE: sensitivity-maximising version (2008 revision) as refer-

encedinChapter6.4.11.1anddetailedinbox6.4.cofthe Cochrane

Handbook for Systematic Reviews of InterventionsVersion 5.0.0 (up-dated February 2008) (Higgins 2008). SeeAppendix 1for the full

search strategy conducted on 26 August 2010.

(3) EMBASE (via OVID) from 2008 onwards

We conducted the search on the EMBASE database (i.e. from

2008) on 26 August 2010. See Appendix 2 for the full search

strategy.

Searching other resources

1. We searched bibliographical references of identified studies

for references to additional studies.

2. We searched clinical trials registries: the WHO

International Clinical Trials Registry Platform (ICTRP) search

portalhttp://apps.who.int/trialsearch/on 26 August 2010. See

Appendix 3.

Although we did not impose language restrictions on included

studies, we did not identify any relevant reports in languages other

than English. We contacted the publisher of an earlier review (

Anthony 1995), that evaluated the effects of immediate versus

delayed reconstruction but we were unsuccessful in obtaining a

copy of the report.

Data collection and analysis

Selection of studies

Two review authors (Nigel DSouza (ND) and Zbys Fedorowicz

(ZF)) independently assessed the abstracts of studies resultingfrom

the searches. We obtained full copies of all relevant and potentially

relevant studies, those appearing to meet the inclusion criteria, and

those for which there were insufficient data in the title and abstract

to make a clear decision. The two review authors independently

assessed the full-text papers and resolved any disagreement on the

eligibility of included studies through discussion and consensus

with the third author (Geraldine Darmanin (GD)). We excluded

allirrelevantrecords andnoted details of thestudies andthe reasons

for their exclusion in theCharacteristics of excluded studiestable

in RevMan 5 (RevMan 2008).

Data extraction and management

We entered study details into the Characteristics of included

studiestable in RevMan 5. We collected outcomes data using a

pre-determined form designed for this purpose andwe entered the

data intoTable 1. We only included data if we reached consensus

or resolved any disagreements by consulting with a third reviewauthor (GD).

We extracted the following details.

1. Trial methods: (a) method of allocation; (b) masking of

participants, trialists and outcomes assessors; (c) exclusion of

participants after randomisation and proportion and reasons for

losses at follow-up.

2. Participants: (a) country of origin and location: private

clinic or academic institute; (b) sample size; (c) age; (d) sex; (e)

inclusion and exclusion criteria.

3. Intervention: (a) type; (b) length of time in follow-up.

4. Control: (a) type; (b) length of time in follow-up.

5. Outcomes: (a) primary and secondary outcomes mentioned

in theTypes of outcome measuressection of this review.If stated, we planned to record the sources of funding.

The review authors intended to use this information to help them

assess heterogeneity and the external validity of the trials.

Assessment of risk of bias in included studies

Each review author assessed and graded the selected trial following

the domain-based evaluation described in the Cochrane Handbook

for Systematic Reviews of Interventions5.0.0 (Higgins 2008). We

compared these evaluations and we resolved any inconsistencies

and disagreements by discussion.

We assessed the following domains as Yes (i.e. low risk of bias),Unclear (i.e. uncertain risk of bias) or No (i.e. high risk of bias):

sequence generation;

allocation concealment;

blinding (of participants, personnel and outcome assessors);

incomplete outcome data; and

selective outcome reporting.

We reported these assessments in the Risk of bias table in the

Characteristics of included studiessection of the review.

Measures of treatment effect

The outcomes we specified for this review were mortality, morbid-

ity, quality of life and included measures of self-esteem andpatient

satisfaction with the procedures. We intended to assess continu-

ous data using standardised mean differences (SMD), and binary

outcomes using odds ratios (OR). We planned to divide outcome

variables reported at different time points into immediate, short

and long term follow-up.


http://apps.who.int/trialsearch/http://apps.who.int/trialsearch/http://apps.who.int/trialsearch/http://apps.who.int/trialsearch/http://apps.who.int/trialsearch/

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Unit of analysis issues

Weexpected that eligible trials may have involved participantswith

bilateral breast reconstruction and therefore the unit of analysis

would have been at the level of randomisation of either the breast

or the individual, whichever was appropriate.

Dealing with missing data

In view of the age of the included study, we did not attempt to

retrieve missing data from the investigators. Missing data were

largely attributable to withdrawals/protocol deviations and thus

we have only provided a descriptive summary of the results as

reported.

Assessment of heterogeneity

We only included one trial in this review, therefore, it was not

feasible to assess heterogeneity but in future updates and if further

trials are identified we will apply the following methods.We will assess clinical heterogeneity by examining the characteris-

tics of the studies, the similarity between the types of participants,

the interventions and the outcomes, as specified in the criteria for

included studies. In view of the expectation of a degree of clinical

heterogeneity between the studies we intend to use the random-

effects model with studies grouped by action.

We will assess statistical heterogeneity using the I2 statistic

(Higgins 2003).

We will evaluate the I2 statistic as follows:

0% to 40%: might not be important;

30% to 60%: may represent moderate heterogeneity;

50% to 90%: may represent substantial heterogeneity;

75% to 100%: considerable heterogeneity.

Assessment of reporting biases

If further eligible studies are identified, we will follow the recom-

mendations on testing for funnel plot asymmetry as described in

section 10.4.3.1 of theCochrane Handbook for Systematic Reviews

of Interventions5.0.0 (Higgins 2008). Funnel plot asymmetry may

be due to reporting bias, and we will address this possibility in the

Discussion if appropriate. We recognise that these results need

to be interpreted cautiously if analysing small study effects with

dichotomous outcomes.

Data synthesis

If adequate data are available in future updates, we will use the

following methods of data synthesis.

Two review authors (ZF and ND) will analyse the extracted data

and report them as specified in Chapter 9 of the Cochrane Hand-

book for Systematic Reviews of InterventionsVersion 5.0.0 (Higgins

2008). Please seeUnit of analysis issues.

The outcomes specified for thisreview include morbidityand qual-

ity of life, therefore, we will make decisions regarding if and how

to combine separate outcomes data depending on if and how this

information is collected in each trial. The data are most likely to

be assessed as ordinal outcome data. However, our decisions for

analysis will be guided explicitly by, and based on,the recommen-dations for dealing with effect measures for ordinal outcomes and

measurement scales in section 9.2.4 of the Cochrane Handbook for

Systematic Reviews of InterventionsVersion 5.0.0 (Higgins 2008).

We will report data and if feasible, we will synthesise the data ac-

cording to this guidance.

We will use the random-effects model for the synthesis and meta-

analysis of any quantitative data.

In the eventthat thereare insufficient clinicallyhomogeneous trials

for any specific intervention or insufficient study data that can be

pooled, we will present a narrative synthesis.

Subgroup analysis and investigation of heterogeneity

Lack of included studies did not permit a subgroup analysis, but

if data are subsequently available for a sufficiently large number of

participants, we will undertake subgroup analyses in which par-

ticipants are categorised by age, staging of breast cancer at time of

diagnosis, and the type of reconstruction performed.

Sensitivity analysis

We did not carry out a sensitivity analysis but if future updates in-

clude a sufficient number of studies, we plan to conduct sensitivity

analyses to assess the robustness of our review results by repeating

the analysis with the following adjustments: exclusion of studies

with unclear or inadequate allocation concealment, blinding of

outcomes assessment and completeness of follow-up.

R E S U L T S

Description of studies

See: Characteristicsof included studies; Characteristicsof excluded

studies.

See: Characteristics of included studies and Characteristics of

excluded studies.

Results of the search

From the electronic searches, including the recent updates (August

2010), we retrieved 411 references to studies. After examination of

thetitlesandabstracts of these references, we eliminated allof those

which did not match our inclusion criteria and those which were

clearly ineligible from the review. We obtained full text copies of


https://mail.google.com/mail/html/compose/staticchar%20%22A8penalty%20z@%20files/CHARACTERISTICSchar%20%22A8penalty%20z@%20OFchar%20%22A8penalty%20z@%20INCLUDEDchar%20%22A8penalty%20z@%20STUDIEShttps://mail.google.com/mail/html/compose/staticchar%20%22A8penalty%20z@%20files/CHARACTERISTICSchar%20%22A8penalty%20z@%20OFchar%20%22A8penalty%20z@%20EXCLUDEDchar%20%22A8penalty%20z@%20STUDIEShttps://mail.google.com/mail/html/compose/staticchar%20%22A8penalty%20z@%20files/CHARACTERISTICSchar%20%22A8penalty%20z@%20OFchar%20%22A8penalty%20z@%20EXCLUDEDchar%20%22A8penalty%20z@%20STUDIEShttps://mail.google.com/mail/html/compose/staticchar%20%22A8penalty%20z@%20files/CHARACTERISTICSchar%20%22A8penalty%20z@%20OFchar%20%22A8penalty%20z@%20EXCLUDEDchar%20%22A8penalty%20z@%20STUDIEShttps://mail.google.com/mail/html/compose/staticchar%20%22A8penalty%20z@%20files/CHARACTERISTICSchar%20%22A8penalty%20z@%20OFchar%20%22A8penalty%20z@%20EXCLUDEDchar%20%22A8penalty%20z@%20STUDIEShttps://mail.google.com/mail/html/compose/staticchar%20%22A8penalty%20z@%20files/CHARACTERISTICSchar%20%22A8penalty%20z@%20OFchar%20%22A8penalty%20z@%20EXCLUDEDchar%20%22A8penalty%20z@%20STUDIEShttps://mail.google.com/mail/html/compose/staticchar%20%22A8penalty%20z@%20files/CHARACTERISTICSchar%20%22A8penalty%20z@%20OFchar%20%22A8penalty%20z@%20EXCLUDEDchar%20%22A8penalty%20z@%20STUDIEShttps://mail.google.com/mail/html/compose/staticchar%20%22A8penalty%20z@%20files/CHARACTERISTICSchar%20%22A8penalty%20z@%20OFchar%20%22A8penalty%20z@%20INCLUDEDchar%20%22A8penalty%20z@%20STUDIEShttps://mail.google.com/mail/html/compose/staticchar%20%22A8penalty%20z@%20files/CHARACTERISTICSchar%20%22A8penalty%20z@%20OFchar%20%22A8penalty%20z@%20INCLUDEDchar%20%22A8penalty%20z@%20STUDIEShttps://mail.google.com/mail/html/compose/staticchar%20%22A8penalty%20z@%20files/CHARACTERISTICSchar%20%22A8penalty%20z@%20OFchar%20%22A8penalty%20z@%20INCLUDEDchar%20%22A8penalty%20z@%20STUDIEShttps://mail.google.com/mail/html/compose/staticchar%20%22A8penalty%20z@%20files/CHARACTERISTICSchar%20%22A8penalty%20z@%20OFchar%20%22A8penalty%20z@%20INCLUDEDchar%20%22A8penalty%20z@%20STUDIES

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the remaining nine potentially eligible trials for furtherevaluation.

The review authors discussed the eligibility of these trials and

resolved any remaining uncertainties by consensus. Subsequently

only one study proved to be eligible for inclusion in this review

and therefore, we excluded the remaining eight studies.

Included studies

We included only one study in this review (Dean 1983).

Characteristics of the trial setting and investigators

This RCT was conducted at the Longmore Hospital, Edinburgh

between October 1978 and July 1980. The providers of care were

hospital staff in the breast surgery unit and the outcomes assessors

were the surgeons, psychiatrists, psychologists and nurse counsel-

lors.

Characteristics of the participants

Theparticipantswere64womenbelowtheageof60,andalthough

the report indicated that there was no significant difference in age,

marital status, TNM (tumour, node, metastasis) staging or treat-

ment options (radiotherapy, chemotherapy and oophorectomy),

the investigators provided very limited demographic information.

Characteristics of the interventions

All of the participants underwent total mastectomy which in-

cluded axillary node clearance for some participants. This was fol-

lowed by immediate reconstruction for 33 participants or the op-

tion of delayed reconstruction at 12 months post-mastectomy for31 participants. A sialastic subpectoral prosthesis (Heyer-Schultz)

was provided for 33 participants at the time of mastectomy. The

31 participants in the delayed reconstruction group were advised

about an external prosthesis and although all patients were offered

delayed reconstruction, only six took up the option 12 months

after mastectomy.

Post-operative care consisted of penicillin V (1 gm/day) and flu-

cloxacillin (1 gm/day) orally for five days. Patients with positive

nodes received either radiotherapy, or chemotherapy/oophorec-

tomy.

Characteristics of the outcome measures

Assessments were made at three and 12 months post-operatively,

which included morbidity across different domains (psychiatric,

sexual, social, marital and work) using Spitzers Research Diagnos-

tic Criteria for major depression or Feighner Criteria for depres-

sion or anxiety. A self-rated general health questionnaire was used

as a screening instrument for psychiatric morbidity.

Cosmetic assessment of the implant group was carried out at

nought to 17 months post-operatively by a panel of two surgeons,

a psychiatrist, a psychologist and a nurse counsellor. A non val-

idated tool was used to evaluate cosmetic outcomes, which in-

cluded assessments of the symmetry of the breast both with and

without a bra, rated on a three-point scale of 5 = good, 3 = average,1 = poor. Patient assessment of cosmetic results using a scale rated

as ugly/not ugly/almost normal were also undertaken 3 and 12

months post-operatively (Table 1).

Excluded studies

All of the studies which were excluded from this review and the

reasons for their exclusion are reported in theCharacteristics of

excluded studiestable.

Risk of bias in included studies

We assessed the single included study as having a high risk of bias(plausible bias that seriously weakens confidence in the results)

because one or more of the criteria were not met. Further details

of the assessments of these criteria are available in the Risk of

bias table in theCharacteristics of included studies and are also

presented in the Risk of bias graph inFigure 1and the Risk of

bias summary inFigure 2.



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Overall completeness and applicability ofevidence

The included RCT was conducted over 25 years ago, limiting its

applicability to current surgical practice. Although sialastic im-

plantsare still used in reconstruction, autologous flaps tend to pro-

vide improved cosmetic outcomes and are more commonly usedin most specialist centres. The review also failed to identify any

RCTs evaluating the evidence for the effectiveness of other types

of implants and some of the other surgical procedures.

Quality of the evidence

Although we considered the included RCT to be of sub-optimal

quality and assessed it as being at high risk of bias, we have reported

its results as it was the only prospective RCT that matched our

inclusion criteria. We are unaware of any unpublished studies, and

currently there are no ongoing RCTs listed on the WHO ICTRP

search portal.

Limitations in study design

The overall clinical design of the included study was inadequate

and we have reported the limitations of its methodological quality

in our assessment of the risk of bias and include the following.

1. Inadequate reporting of the methods used to generate the

sequence, to conceal the allocation in addition to a lack of

adequate measures to blind outcomes assessors. The lack of

available additional or incomplete trial information and data

prevented an accurate assessment of the risk of bias.

2. Outcome data were either incomplete or not clearly

reported which meant that we could not enter data into aRevMan analysis.

Directness of evidence

Participants in the control group in the included study were given

the option to forego reconstruction at a later date. Twenty-five of

the 31 participants did not proceed to reconstruction, resulting

in the trial failing to provide a reliable direct comparison of the

benefits of immediate versus delayed reconstruction.

Moreover, in view of the low take-up of delayed reconstruction

any direct comparisons of, for example, the cosmetic effects of

immediate versus no reconstruction, cannot be considered a fair

comparison and would thus limit the generalisability of any evi-

dence. This holds equally true for the comparisons of complica-

tions of surgery with immediate versus no reconstruction, because

it would not be possible to include assessments of complications

after delayed reconstructive surgery.

Patient-preferred primary outcomes are a pre-requisite for inform-

ing evidence-based clinical decision-making and thus the absence

of data from RCTs on certain patient-important outcomes i.e. as-

sessments of post-operative morbidity (number of surgical com-

plications) and mortality justifies further downgrading of the level

of evidence.

Inconsistency of results

As only one RCT was included in this review, this assessment was

not applicable.

Imprecision of results

The limited amount of outcome data available from this single

trial did not permit any assessment of the precision of the results.

Probability of publication bias

We could not estimate publication bias as only one trial was in-

cluded in this review.

Potential biases in the review process

We did not identify any sources of potential bias in the review

process.

Agreements and disagreements with otherstudies or reviews

This reviewshares some of the conclusions reachedby other cohort

studies and reviews (Atisha 2009; Fischbacher 2002; Harcourt

2001) which have focused on this research question. All of thesehave emphasised the considerable heterogeneity in participants in

individual studies and between studies. They also found a paucity

of methodologically rigorous research exploring clinical and psy-

chosocial outcomes following immediate or delayed breast recon-

struction. The majority of studies conducted have been retrospec-

tive analyses. Prospective studies that have been conducted lack

comparison or control groups, and have reported outcomes that

have been evaluated using different questionnaires or assessment

tools, and therefore do not permit fair comparisons or synthesis

of data. Much of this evidence from prospective trials is based on

cohort studies (Al-Ghazal 2000;Alderman 2002;DeBono 2002;

Francel 1993;Mandrekas 1995).

One systematic review (Fischbacher 2002) included a series of co-

hort studies in addition to a single RCT (Dean 1983) which, in

contrast to our assessment, the authors considered to be of mod-

erate quality. The conclusions reached in a more recent system-

atic review (Guyomard 2007) pointed to the very limited number

of studies evaluating important patient reported outcomes (PRO)

of patient satisfaction. The review authors also reported multiple

flaws in methodology of the few included trials which made their



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analysis difficult and limited the validity and subsequent general-

isability of any of their results. However, in agreement with our

review, the authors stated that further research is required and that

future trials should be robust in quality to ensure reliable assess-

ment of relevant patient-preferred outcomes.

The summary in a literature review (Harcourt 2001) indicated

that there was still uncertainty about which treatment confers the

greatest psychological benefit and that further research needs to

consist of studies with a multi-centred prospective design com-

bining both qualitative and quantitative components. In contrast

with most of these reviews the investigators in a prospective cohort

study reported psychosocial benefits and body image gains which

persisted at two years following immediate reconstruction (Atisha

2009). Although we were unable to obtain copies of an earlier

review (Anthony 1995) which evaluated the effects of immediate

versus delayed reconstruction, this review had been assessed by

Fischbacher 2002who reported a number of methodological lim-

itations including the lack of a systematic assessment of the qualityand relevance of studies.

A U T H O R S C O N C L U S I O N S

Implications for practice

We included only one RCT that, which did not consider our pri-

mary outcome of post-operative surgical complications and only

partially addressed our pre-specified secondary outcomes of psy-

chosocial well-being post-reconstruction in this review. The find-

ing that immediate reconstruction reduced psychiatric morbidityat three months should only be accepted while acknowledging

the methodological shortcomings and high risk of bias inherent

in the trial. The application of these findings is further limited

given that the surgical technique for immediate reconstruction in

this 27-year old trial is not current recommended practice. Un-

fortunately, the very limited number of study participants in the

control (delayed intervention) group in the included study who

later decided to undergo reconstruction were not analysed and

the results of this subgroup might have shed light on important

psychological or cosmetic outcomes. The included trial provides

very limited evidence which is likely to inform decision-making

in clinical practice.

Implications for research

The paucity of relevant trials, illustrated by a single study carried

out over25 yearsago,points tothe need for furtherresearch inthis

field. One of the main barriers to further research would appear

to be that the benefits of post-operative radiotherapy to the breast

are well known with regards to recurrence (Whelan 2000), if not

on overall mortality (Early Breast Cancer Trialists Collaborative

Group). Immediate reconstruction may not be carried out if ra-

diotherapy is planned, with its recognised and potentially adverse

aesthetic outcomes.

Constraints in terms of study design, and in particular RCTs, hasmeant that much of the previous research consists of cohort stud-

ies, audits and surveys rather than large-scale trials. The inade-

quate methodological quality of many of these was highlighted in

Guyomard 2007, and in spite of this, there is well-documented

resistance to RCTs in the evaluation of psychological outcomes

for these interventions (Atisha 2009;Harcourt 2001). The ethical

obstacles to randomised trials have been attributed to the removal

of womens input into decision-making (Harcourt 2001). This re-

port found that inDean 1983, a lack of participant control over

the timing or type of reconstruction raises serious ethicalconcerns,

since involvement in decision-making may be a crucial factor in

improving psychological outcomes.

However, given that RCTs have been and are still being conducted

in surgical domains where shared clinical decision-making is still

the norm, and have yielded valuable information, the question is

why this should not be possible in breast reconstruction. Since

RCTs remain the most reliable study design to remove confound-

ing and sources of bias, modifications such as the Zelens design

with double randomised consent may have implications for future

research.

Future randomised controlled trials must be well designed, con-

ducted and adequately delivered with subsequent reporting, in-

cluding high quality descriptions of all aspects of methodology.

Rigorous reporting needs to conform to the Consolidated Stan-

dards of Reporting Trials (CONSORT) statement (www.consort-statement.org/) andthis will enable appraisal and interpretation of

results, and accurate judgements to be made about the risk of bias

and the overall quality of the evidence. Although it is uncertain

whether reported quality mirrors actual study conduct, it is note-

worthy that studies with unclear methodology have been shown to

produce biased estimates of treatment effects (Schulz 1995). Ad-

herence to guidelines, such as the CONSORT statement, would

help ensure complete reporting.

For further research recommendations based on the EPICOT for-

mat (Brown 2006) please see (Table 2).

A C K N O W L E D G E M E N T S

The authors would like to acknowledge the support they have

received from the Cochrane Breast Cancer Group in conducting

this review.


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R E F E R E N C E S

References to studies included in this review

Dean 1983 {published data only}

Dean C, Chetty U, Forrest APM. Effects of immediate

breast reconstruction on psychosocial morbidity aftermastectomy. Lancet1983;1(8322):45962.

References to studies excluded from this review

Alderman 2002 {published data only}

Alderman AK, Wilkins EG, Kim HM, Lowery JC.

Complications in postmastectomy breast reconstruction:

two-year results of the Michigan Breast Reconstruction

Outcome Study. Plastic and Reconstructive Surgery2002;

109(7):226574. [PUBMED: 12045548]

Atisha 2009 {published data only}

Atisha D, Alderman AK, Janiga T, Singal B, Wilkins EG.

The efficacy of the surgical delay procedure in pedicle

TRAM breast reconstruction. Annals of Plastic Surgery

2009;63(4):3838. [PUBMED: 19770703]

Cheng 2006 {published data only}

Cheng MH, Lin JY, Ulusal BG, Wei FC. Comparisons

of resource costs and success rates between immediate

and delayed breast reconstruction using DIEP or SIEA

flaps under a well-controlled clinical trial. Plastic and

Reconstructive Surgery2006;117(7):213942.

Fernandez-Delgado 2008 {published data only}

Fernandez-Delgado J, Lopez-Pedraza MJ, Blasco JA,

Andradas-Aragones E, Sanchez-Mendez JI, Sordo-Miralles

G, et al.Satisfaction with and psychological impact of

immediate and deferred breast reconstruction. Annals of

Oncology2008;19(8):14304. [PUBMED: 18390839]

Harcourt 2003 {published data only}Harcourt DM, Rumsey NJ, Ambler NR, Cawthorn SJ,

Reid CD, Maddox PR, et al.The psychological effect of

mastectomy with or without breast reconstruction: a

prospective, multicenter study. Plastic and Reconstructive

Surgery2003;111(3):10608. [PUBMED: 12621175]

Neyt 2005 {published data only}

Neyt MJ, Blondeel PN, Morrison CM, Albrecht JA.

Comparing the cost of delayed and immediate autologous

breast reconstruction in Belgium. British Journal of Plastic

Surgery2005;58(4):4937. [PUBMED: 15897033]

Roth 2007 {published data only}

Roth RS, Lowery JC, Davis J, Wilkins EG. Persistent pain

following postmastectomy breast reconstruction: long-

term effects of type and timing of surgery. Annals of Plastic

Surgery2007;58(4):3716. [PUBMED: 17413877]

Wilkins 2000 {published data only}

Wilkins EG, Cederna PS, Lowery JC, Davis JA, Kim HM,

Roth RS, et al.Prospective analysis of psychosocial outcomes

in breast reconstruction: one-year postoperative results

from the Michigan Breast Reconstruction Outcome Study.

Plastic and Reconstructive Surgery2000;106(5):1014-25;

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DeBono 2002

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radiotherapy and cytotoxic chemotherapy on the outcome

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Whitfield GA, Horan G, Irwin MS, Malata CM, Wishart

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Indicates the major publication for the study



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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Dean 1983

Methods Randomised control led trial in Longmore Hospital Edinburgh between October 1978

and July 1980

Participants N = 64 women, age unspecified but all under 60 years.

INCLUSION CRITERIA:

primary operable breast cancer (T12N01) requiring mastectomy;

no metastatic disease (normal pelvis/chest x rays, bone and liver isotope scans and

liver function tests).

EXCLUSION CRITERIA:

over 60 years;

non-operable breast cancer;

metastatic disease.

WITHDRAWALS/LOSSES TO FOLLOW-UP:

Immediate Group: 2 withdrawals after randomisation (1) not reconstructed for technical

reasons feasible, (1) had implant accidentally aspirated post-operatively

Delayed Group: withdrawals (25) i.e. chose no reconstruction.

Interventions Total mastectomy (with axillary node clearance for some participants), followed by im-

mediate reconstruction compared with an option of delayedreconstruction at 12 months

INTERVENTION:

(31/33) sialastic subpectoral prosthesis (Heyer-Schultz).

Post -op care: penicillin V (1 gm/day) and flucloxacillin (1 gm/day) orally for 5 days.

Participants with positive nodes received radiotherapy, node-positive and premenopausal

received chemotherapy or oophorectomyCONTROL:

(6/31) opted for delayed reconstruction.

Outcomes PRIMARY OUTCOMES:

No post-operative morbidity or mortality was reported.

SECONDARY OUTCOMES:

cosmetic appearance assessed at 9 to 17 months by investigators and panel of

assessors (3-point scale: 5 = good, 3 = average, 1 = poor);

psychological assessments by interview at 3 and 12 months, psychiatric, sexual,

social, marital, and work morbidity;

participants completed a general health questionnaire.

ADVERSE EVENTS: No reporting of long term post-op complications or adverse events

Notes The comparisons were mastectomy with immediate reconstruction versus mastectomy

and optional delayed reconstruction.

Unclear if the evaluations included the 6/31 in the delayed reconstruction (12 months

post mastectomy) group

Risk of bias



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Dean 1983 (Continued)

Bias Authors judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk Quote: were randomly allocated Thepatient was then randomised in the oper-

ating room to either receive an implant or

not. were randomly selected.... Pg 459.

Comment: Insufficient information in the

report about the method use to generate

the allocation sequence

Allocation concealment (selection bias) Unclear risk The method used to conceal the allocation

sequence, that is to determine whether in-

terventionallocations couldhave been fore-

seen in advance of, or during enrolment,

was not reported.

Comment: Insufficient information to per-mit judgement Yes or No

Blinding (performance bias and detection

bias)

All outcomes

High risk Participants: not possible to blind.

Healthcareproviders: not possible to blind.

Outcomes assessors and data analysts: un-

clear who were the outcomes assessors, but

at least some were investigators. Unclear if

the data analysts were blinded

Incomplete outcome data (attrition bias)

All outcomes

High risk 2 participants (implant group) were not

seen for pre-operative psychiatric assess-

ments.No post -operative data for the delayed re-

construction group(6/31), and missingfol-

low-up data for 4 participants in the im-

mediate reconstruction group.

Cosmetic appearance of patients with im-

plants assessments at 9 to 17 months, un-

clear whetherthisdataincludedthe delayed

implant group (6).

General Health Questionnaire:Incomplete

data 14/64 (22%) at follow up, but unclear

from which group and the reasons.

Data analysis didnot conform to ITTprin-

ciples.

Selective reporting (reporting bias) Low risk The stated objectives of the study appeared

to match the reported outcomes

Other bias High risk Possible sampling bias at enrolment. Ran-

domisation to reconstruction or no recon-

struction occurred after the mastectomy



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Dean 1983 (Continued)

procedure, the possibility of selection bias

cannot be ruled out

ITT: intention-to-treat

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Alderman 2002 Non RCT, prospective cohort.

Atisha 2009 Non RCT, retrospective.

Cheng 2006 Non RCT.

Fernandez-Delgado 2008 Non RCT, questionnaire.

Harcourt 2003 Non RCT.

Neyt 2005 Non RCT.

Roth 2007 Non RCT.

Wilkins 2000 Non RCT, prospective cohort study.

RCT: randomised controlled trial



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D A T A A N D A N A L Y S E S

Comparison 1. Immediate versus delayed reconstruction

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Data that cannot be presented

graphically in Revman

Other data No numeric data

Analysis 1.1. Comparison 1 Immediate versus delayed reconstruction, Outcome 1 Data that cannot be

presented graphically in Revman.

Data that cannot be presented graphically in Revman

Study Participants Interventions Outcomes Notes

Dean 1983 64 women,

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A D D I T I O N A L T A B L E S

Table 1. Participants cosmetic evaluations at 3 and 12 months

Assessment 3 months 12 months

Implant No implant Implant No Implant

Ugly 11 20 8 17

Not ugly 11 8 21 11

Almost Normal 8 2 2 1

Total 30 30 31 29

64 randomised: 31 immediate reconstruction, 6/33 delayed reconstruction (Data inconsistently unreported)

Table 2. Research recommendations based on a gap in the evidence of immediate versus delayed reconstruction following

surgery for breast cancer

Core elements Issues to consider Status of research for this review

Evidence

(E)

What is the current state of evidence? A systematic review found very limited reliable evidence

for the benefits or harms of immediate compared with

delayed reconstruction following surgery for breast can-

cer

Population

(P)

Diagnosis, disease stage, comorbidity, risk factor, sex,

age, ethnic group, specific inclusion or exclusion crite-ria, clinical setting

Any age group with a diagnosis of primary operable

breast cancer requiring mastectomy, without evidenceof metastatic disease (normal pelvis/chest x-rays, bone

and liver isotope scans and liver function tests)

Exclusion criteria:

non-operable breast cancer,

metastatic disease.

To limit geographical and cultural biases and ensure a

wider generalisability of the evidence, greater empha-

sis should be placed on a more culturally diverse pop-

ulation and which may include multi-centred interna-

tional settings for future studies

Intervention

(I)

Type, frequency, dose, duration, prognostic

factor

Total mastectomy (with/without axillary node clear-

ance), followed by immediate reconstruction with anautologous flap and/or any other form of implant

Comparison

(C)

Type, frequency, dose, duration, prognostic

factor

Delayed reconstruction at 12 months.

Outcome

(O)

Which clinical or patient related outcomes will the re-

searcher need to measure, improve, influence or accom-

Clinical outcomes:

mortality,



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Table 2. Research recommendations based on a gap in the evidence of immediate versus delayed reconstruction following

surgery for breast cancer (Continued)

plish?

Which methods of measurement should be used?

intra and post operative complications/adverse

events.

Patient-preferred outcomes: quality of life, emotional and psychological

morbidity, cosmetic appearance (assessed with

validated generic or disease-specific assessment tools).

Time Stamp

(T)

Date of literature search or recommendation EMBASE and Medline till 26th August 2010, ICTRP

and Cochrane Breast Cancer Groups Specialised Reg-

ister till 22nd July 2010

Study Type What is the most appropriate study design to address

the proposed question?

Randomised controlled trial (adequately powered) with

up to a 5 year follow-up

Methods:concealment of allocation sequence

Blinding: Not possible to blind participants or care

givers but outcomes assessors and data analysts shouldbe blinded

Setting:Specialised surgical/ plastic surgery unit.

A P P E N D I C E S

Appendix 1. MEDLINE search strategy (via Ovid)

1. randomised controlled trial.pt.2. controlled clinical trial.pt.

3. randomized.ab.

4. randomised.ab

5. placebo.ab.

6. randomly.ab.

7. trial.ab.

8. groups.ab.

9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8

10. exp Breast Neoplasms/

11. (breast adj6 cancer$).mp.

12. (breast adj6 neoplasm$).mp.

13. (breast adj6 carcinoma$).mp.

14. (breast adj6 tumour$).mp.15. (breast adj6 tumor$).mp.

16. 10 or 11 or 12 or 13 or 14 or 15

17. exp Reconstructive Surgical Procedures/

18. exp Breast Implants/

19. exp Prostheses and Implants/

20. exp Mammaplasty/

21. exp Surgical Flaps/

22. (breast adj6 reconstruct$).mp.



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23. (breast adj6 reconstruct$ adj6 surger$).mp.

24. (breast adj6 reconstruct$ adj6 surgical adj6 procedure$).mp.

25. (immediate$ adj6 breast adj6 reconstruct$).mp.

26. (immediate$ adj6 breast adj6 reconstruct$ adj6 surger$).mp.

27. (immediate$ adj6 breast adj6 reconstruct$ adj6 surgical adj6 procedure$).mp.

28. (delay$ adj6 breast adj6 reconstruct$).mp.29. (delay$ adj6 breast adj6 reconstruct$ adj6 surger$).mp.

30. (delay$ adj6 breast adj6 reconstruct$ adj6 surgical adj6 procedure$).mp.

31. 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30

32. exp Mastectomy/

33. (post$ adj6 mastectom$).mp.

34. 32 or 33

35. 9 and 16 and 31 and 34

36. limit 35 to humans

Appendix 2. EMBASE Search Strategy (Ovid SP format)

1. exp breast cancer/2. breast tumor/

3. exp neoplasm/ and medullary.mp.

4. exp fibrocystic breast disease/

5. 1 or 2 or 4 or 3

6. exp breast/

7. breast.tw.

8. 7 or 6

9. (breast adj milk).ti,ab,sh.

10. (breast adj tender$).ti,ab,sh.

11. 9 or 10

12. 8 not 11

13. exp neoplasm/

14. 12 and 1315. exp lymphedema/

16. 14 and 15

17. (breast adj25 neoplasm$).ti,ab,sh.

18. (breast adj25 cancer$).ti,ab,sh.

19. (breast adj25 tumour$).ti,ab,sh.

20. (breast adj25 tumor$).ti,ab,sh.

21. (breast adj25 carcinoma$).ti,ab,sh.

22. (breast adj25 adenocarcinoma$).ti,ab,sh.

23. (breast adj25 sarcoma$).ti,ab,sh.

24. (breast adj25 dcis).ti,ab,sh.

25. (breast adj25 ductal).ti,ab,sh.

26. (breast adj25 infiltrating).ti,ab,sh.

27. (breast adj25 intraductal).ti,ab,sh.28. (breast adj25 lobular).ti,ab,sh.

29. (breast adj25 medullary).ti,ab,sh.

30. or/17-29

31. 5 or 14 or 30 or 16

32. exp mastectomy/

33. 31 or 32

34. exp mammary neoplasms/

35. (mammary adj25 neoplasm$).ti,ab,sh.



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36. (mammary adj25 cancer$).ti,ab,sh.

37. (mammary adj25 tumour$).ti,ab,sh.

38. (mammary adj25 tumor$).ti,ab,sh.

39. (mammary adj25 carcinoma$).ti,ab,sh.

40. (mammary adj25 adenocarcinoma$).ti,ab,sh.

41. (mammary adj25 sarcoma$).ti,ab,sh.42. (mammary adj25 dcis).ti,ab,sh.

43. (mammary adj25 ductal).ti,ab,sh.

44. (mammary adj25 infiltrating).ti,ab,sh.

45. (mammary adj25 intraductal).ti,ab,sh.

46. (mammary adj25 lobular).ti,ab,sh.

47. (mammary adj25 medullary).ti,ab,sh.

48. or/34-47

49. 33 or 48

50. (breast adj6 reconstruct$).mp.

51. (breast adj6 reconstruct$ adj6 surger$). ti,ab,sh.

52. (breast adj6 reconstruct$ adj6 surgical adj6 procedure$). ti,ab,sh.

53. (immediate$ adj6 breast adj6 reconstruct$). ti,ab,sh.

54. (immediate$ adj6 breast adj6 reconstruct$ adj6 surger$). ti,ab,sh.55. (immediate$ adj6 breast adj6 reconstruct$ adj6 surgical adj6 procedure$). ti,ab,sh.

56. (delay$ adj6 breast adj6 reconstruct$). ti,ab,sh.

57. (delay$ adj6 breast adj6 reconstruct$ adj6 surger$). ti,ab,sh.

58. (delay$ adj6 breast adj6 reconstruct$ adj6 surgical adj6 procedure$). ti,ab,sh.

59. or/50-58

60. 49 and 59

61. exp controlled clinical trial/

62. comparative study/

63. drug comparison/

64. randomization/

65. crossover procedure/

66. double blind procedure/

67. single blind procedure/68. placebo/

69. prospective study/

70. ((clinical or controlled or comparative or placebo or prospective or randomi#ed) adj3 (trial or study)).ti,ab.

71. (random$ adj7 (allocat$ or allot$ or assign$ or basis$ or divid$ or order$)).ti,ab.

72. ((singl$ or doubl$ or trebl$ or trip$) adj7 (blind$ or mask$)).ti,ab.

73. (cross?over$ or (cross adj1 over$)).ti,ab.

74. or/61-73

75. 60 and 74

76. limit 75 to human

77. limit 76 to yr=2003 - 2010



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Appendix 3. WHO ICTRP Search

WHO ICTRP Search (22/07/2010)

1. Title: breast reconstruction OR immediate breast reconstruction OR immediate reconstruction OR delay* breast reconstruction OR

delay* reconstruction OR postmastectomy OR postmastectomies OR post mastectomy OR post mastectomies OR post-mastectomy

OR post-mastectomies OR Latissimus Dorsi Myocutaneous Flap OR Latissimus Dorsi Myocutaneous Flaps OR TRAM Flap OR

TRAM Flaps OR Deep Inferior Epigastr

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