preventing pharyngo-cutaneous fistula in total ... · total laryngectomy alone, or total...

The LaryngoscopeVC 2013 The American Laryngological,Rhinological and Otological Society, Inc.

Systematic Review

Preventing Pharyngo-Cutaneous Fistula in Total Laryngectomy:

A Systematic Review and Meta-Analysis

Mark Sayles, MB, BChir, MA, PhD; David G. Grant, MB, ChB, BSc, FRCS

Objectives/Hypothesis: Concurrent chemoradiotherapy is the gold-standard nonsurgical organ-preservation treatmentfor advanced laryngeal carcinoma. Total laryngectomy (TL) is increasingly reserved for surgical salvage. Salvage surgery isassociated with more complications than primary surgery. A systematic review and meta-analysis was undertaken to establishthe impact of organ preservation protocols on pharyngo-cutaneous fistula incidence following TL, and to synthesize evidenceon the role of “onlay” prophylactic tissue flaps in reducing this complication in salvage TL.

Data Sources: The English language literature (January 1, 2000, to September 1, 2013) was searched, using PUBMEDand EMBASE databases, for the terms “laryngectomy” and “fistula.” Of 522 studies identified from database searches, 33 wereincluded in the quantitative synthesis.

Review Methods: Studies reporting fistula incidence following primary TL (PTL), salvage TL (STL), and STL with“onlay” flap-reinforced pharyngeal closure were included. Data were extracted by the first author (M.S.). Meta-analysis of fis-tula incidence was performed.

Results: PTL fistula incidence is 14.3% (95% CI 11.7–17.0), STL 27.6% (23.4–31.8), and STL with flap-reinforced clo-sure 10.3% (4.6–15.9). Chemoradiotherapy is associated with a pooled fistula incidence of 34.1% (22.6–45.6), compared to22.8% (18.3–27.4) for radiotherapy alone. Relative risk of fistula is 0.566 (0.374–0.856, P50.001) for STL with flap-reinforced closure compared to STL alone. The number needed to treat (NNT) to prevent one fistula is 6.05.

Conclusion: Prophylactic flaps used in an “onlay” technique reduce fistula incidence in STL. Chemoradiotherapyincreases fistula incidence more than radiotherapy alone. Prophylactic flaps should be offered in salvage cases after failedchemoradiation protocols.

Key Words: Laryngectomy; chemotherapy; radiotherapy; salvage surgery; pharyngo-cutaneous fistula; prophylactic; flap.Level of Evidence: 3A.

Laryngoscope, 124:1150–1163, 2014

INTRODUCTIONThe last 2 decades have seen radical changes in the

management of laryngeal carcinoma. Organ-preservationprotocols with radiotherapy alone or combined chemora-diotherapy are now a well-established option for mostpatients with locally advanced disease.1–3 The goal is tomaintain speech and swallowing function while control-ling disease. However, in a proportion of patients thisnonsurgical approach fails, necessitating salvage surgery

in the form of total laryngectomy. Rates of salvage totallaryngectomy (STL) following radiotherapy alone arebetween 31% and 36%, and following chemoradiotherapybetween 16% and 28%.2,4 Chemotherapy exacerbates theobliterative endarteritis and fibrosis induced by radiationin local tissues. This microvascular damage results in tis-sue hypoxia, impairs wound healing,5–9 and has profoundconsequences for surgical salvage.4,10–12

The most common major wound complication follow-ing laryngectomy is the development of a pharyngo-cutaneous fistula (PCF), an abnormal communicationbetween the pharynx and skin through which salivaleaks.13 A meta-analysis identified prior radiotherapy,prior tracheostomy, and postoperative serum hemoglobinlevel< 12.5g/dL as the only independent risk factors forPCF.13 The incidence of PCF is increased in STL com-pared to primary total laryngectomy (PTL), due to theimpaired healing characteristic of irradiated tissues inthe salvage setting.13,14 Reported PCF incidence rates inSTL vary between 14% and 61%.15,16 Development of aPCF is associated with delay in adjuvant treatment, pro-longed hospital stay, requirement for reoperation in ahighly comorbid patient group, and mortality from, for

From the Department of Otolaryngology–Head and Neck Surgery,Queen’s Medical Centre, Nottingham University Hospitals’ NHS Trust,Nottingham, United Kingdom.

Editor’s Note: This Manuscript was accepted for publicationSeptember 23, 2013.

Portions of this work have been presented as a podium presenta-tion at Laryngology & Rhinology short papers meeting, The Royal Soci-ety of Medicine, London, UK, February 1, 2013.

The authors have no funding, financial relationships, or conflictsof interest to disclose.

Send correspondence to Dr. Mark Sayles, Department of Otolaryn-gology–Head and Neck Surgery, Queen’s Medical Centre, NottinghamUniversity Hospitals’ NHS Trust, Nottingham, NG7 2UH, UK. E-mail:[email protected]

DOI: 10.1002/lary.24448

Laryngoscope 124: May 2014 Sayles and Grant: Prophylactic Flaps in Total Laryngectomy

1150

example, carotid blowout or aspiration pneumonia.17

The increased incidence of postlaryngectomy PCF in themodern era of organ-preservation therapy has drivenconsiderable efforts to develop techniques to reduce thisrisk.

Several observational studies have investigated therole of prophylactic vascularized flaps to aid pharyngealclosure following STL, with variable results.16,18–26 Therationale is to place nonirradiated, vascularized tissueover the pharyngeal suture line in an “onlay” techniqueto improve wound healing even when sufficient pharyn-geal mucosa for primary closure remains. In this sense,the flap is used to “reinforce” the pharyngeal closure. Itis not incorporated into the pharyngeal closure. Otherauthors have described using prophylactic “interposition”grafts.26,27 These two techniques are fundamentally dif-ferent. This meta-analysis is limited to the “onlay” tech-nique. Some authors have shown a significant decreasein PCF incidence with “onlay” flap-reinforced pharyngealclosure compared to primary closure alone.16,23–25 Othershave shown more modest effects, with a decrease in thesize of fistulae and associated complications, but no sig-nificant difference in PCF incidence.19,20 There is signifi-cant institutional variation in the closure of STL defects,and neither consensus nor evidence on the precise roleof prophylactic vascularized tissue transfer.11

Through a meta-analysis of observational studies ofoutcomes following laryngectomy, this article summarizesthe available evidence on PCF incidence in STL and PTL,and synthesizes evidence on the role of prophylactic“onlay” flaps for reducing PCF incidence in STL.

MATERIALS AND METHODS

Data Sources, Inclusion Criteria, andLiterature Screening

The English language literature was searched using PUBMEDand EMBASE databases with the keywords “laryngectomy” and“fistula” from January 1, 2000, to September 1, 2013. The rationalefor these inclusion dates is to provide a contemporary view of fistulaincidence in the current epoch of organ-preservation therapy forlaryngeal carcinoma. It is well recognized that the paradigm for lar-yngectomy has changed substantially over the last 2 decades sincethe widespread uptake of organ-preservation therapy in the wake ofboth the Veterans Affairs Laryngeal Cancer Study and RTOG-91-11trials.2,3 Laryngectomy is increasingly reserved for surgical salvage,and it is in view of the increased fistula incidence in this populationthat surgeons have explored prophylactic flaps as a means of mitigat-ing against this problem.4,28

The PRISMA29 guidelines are used for reporting through-out. Only studies meeting strict inclusion criteria were included(Table I). These are: 1) Site. Only studies reporting data frompatients with primary squamous cell carcinoma of the larynx orhypopharynx were included. 2) Procedure. Only studies report-ing data from patients undergoing total laryngectomy or totallaryngectomy and partial pharyngectomy were included. 3) Clo-sure. Only studies reporting data from patients receiving pri-mary pharyngeal closure were included. 4) Study size. Onlystudies reporting data from at least 10 patients were included.5) Follow up. Only studies reporting at least 3 months of post-operative follow-up on all patients were included.

Included studies reported data from at least one of threecategories: PTL, STL with primary pharyngeal closure, and/or

STL with primary pharyngeal closure with a reinforcing tissueflap. A tissue flap was defined as either a regional pedicled flapor vascularized free tissue transfer. It is important to note thatthe analysis is limited to flaps used in an “onlay” technique.

Abstracts from all articles identified in the search werereviewed. Those containing relevant information were obtained forfull review and data extracted by the first author (M.S.) (Fig. 1).

Quality AssessmentThere is no widely accepted quality-assessment metric

available for case series. Therefore, we assessed quality usingone of the forms issued by the National Institute for Health andClinical Excellence (Table II). The minimum and maximumscores possible are 0 and 8, respectively. This same quality met-ric has been used in other recent and similar meta-analyses ofobservational studies.30

Statistical AnalysisAlthough meta-analysis is most commonly thought of as a

method of analyzing the pooled effects of multiple randomizedcontrolled trials, it is also a valid method of performing system-atic review of observational studies with binary outcomes (i.e.,fistula or no fistula).31 The proportion of patients developing afistula was calculated for each study and pooled estimates ofPCF incidence calculated. For studies in which the fistula inci-dence was zero, we implemented continuity correction with afactor of 0.5.32 Therefore, the reported proportion in these casesis not zero, despite there being a zero event rate in the rawdata. Consider a study with zero events in a population of 10.After continuity correction, with 0.5 added to both the “event”

TABLE I.Inclusion Criteria for Articles Selected for Review.

1. Patients underwent laryngectomy for a diagnosis of laryngeal orhypopharyngeal carcinoma.

2. Clear statement on the surgical procedure undertaken: eithertotal laryngectomy alone, or total laryngectomy with partialpharyngectomy.

3. Clear statement that all patients had primary closure of thepharynx.

4. At least 10 patients included in the analysis.

5. At least 3 months follow-up from time of surgery.

Fig. 1. Study identification and attrition flowchart.


1151

and ”no event” categories, the event proportion becomes 0.5/(10.5 1 0.5) 5 0.045. Continuity correction is required in meta-analyses with very high (e.g., 1) or very low (e.g., 0) event rates.The rationale is to approximate a discrete distribution througha continuous one.

The combined summary estimate of the incidence of fistulain each patient group, and of the effect of vascularized flap-reinforced pharyngeal closure, was then calculated from a ran-dom effects model using the method of DerSimonian andLaird.33 The relative risk (RR) of PCF was calculated for eachstudy which included both a no-flap control group and a withflap experimental group. The significance of heterogeneitybetween studies was assessed using the v2 and I2 statistics.Analyses was performed using freely available software:“OpenMeta[Analyst]” from Brown University, available atwww.cebm.brown.edu/open_meta.34,35 Statistical significance ofdifference in group means was assessed with Welch’s t testimplemented using custom-written code in MATLAB (TheMathworks, Inc., Natick, MA), with P<0.05 considered signifi-cant for group comparisons. Meta-regression analysis using arandom-effects model was implemented in “OpenMeta[Analyst]”to examine the impact of patient-related and study-related fac-tors on effect size. The number needed to treat (NNT) to pre-vent one fistula with a prophylactic flap in the STL group isdefined as 1/(PNF–PF), where PNF is the proportion of patientsdeveloping a fistula in the no flap group, and PF is the propor-tion developing a fistula in the flap group.

Assessment for Publication BiasFunnel plots were plotted with 95% and 98% confidence

intervals, based on the binomial distribution. Data wereassessed for asymmetry, and therefore potential publicationbias, using Egger’s statistic implemented in custom-writtenMATLAB code (P<0.05 significant).36 This involves linearregression of the standard normal deviate on the precision (1/standard error), and assessment of the y-axis intercept. If theintercept is significantly different from zero, this suggestsasymmetry. Cumulative meta-analyses were also used to assessfor possible publication bias by virtue of a systematic drift inthe cumulative overall estimate with the addition of smallerstudies.37,38 Meta-influence plots were used to assess for thedominance of any single study in the overall effect.

RESULTS

Study SelectionAfter elimination of duplicates, 522 studies were

identified with the keywords Laryngectomy and Fistula

published between January 1, 2000 and September 1,2013. Thirty-three studies were included in the meta-analyses. Quality scores were between 4 and 7 of 8(Table II, Table III). The majority of excluded studieswere excluded because they contained no relevant infor-mation. Most of these were identified in the searchbecause they were on the subjects of either tracheo-oesophageal puncture for valve-aided speech, or themanagement of fistulae following laryngectomy (Fig. 1).

The majority of data included were from retrospec-tive observational studies reporting outcomes followinglaryngectomy. Data from one randomized controlled trial(RTOG 91-11) were included.4 However, the randomiza-tion of this study was not on the basis of closure tech-nique. Therefore, the data can be considered equivalentto those from an observational study for the purposes ofmeta-analysis. Seven studies compared two groups ofpatients: STL with primary pharyngeal closure as a con-trol arm and STL with primary pharyngeal closure withan “onlay” flap as the experimental arm. The remainingstudies contained data on only one patient group, eitherPTL or STL with or without flap-reinforced closure.

Fistula Incidence: Primary Total LaryngectomyVersus. Salvage Total Laryngectomy

The pooled estimate of fistula incidence followingPTL with primary pharyngeal closure is 14.3% (95% CI11.7–17.0) (Fig. 2A). In total, 326 of 2177 patients under-going PTL developed a fistula. There is significant heter-ogeneity between studies (Q 5 41.83, df 5 15, P< 0.001,I2 5 64%). Meta-influence analysis (Fig. 2B) shows thatno single study dominates the overall estimate. With theaddition of each study in order of decreasing N in acumulative meta-analysis, there is an initial drift towarda smaller estimate of fistula incidence from thatreported in the largest study by Herranz et al.,40 andthen a slight drift toward a marginally higher estimate,with the addition of subsequent small studies (Fig. 2C).The drift is small and does not suggest risk of publica-tion bias.

Figure 3 shows meta-analyses of studies reportingfistula incidence following STL. After STL with primarypharyngeal closure (following either radiotherapy alone,induction chemotherapy with radiotherapy, or concur-rent chemoradiotherapy), the estimated overall fistulaincidence is 27.6% (23.4–31.8), double that seen in thePTL group. In total, 443 of 1721 patients undergoingSTL developed a fistula. Comparing the overall estimatefor PTL and STL groups, the fistula incidence is signifi-cantly higher in the STL group (Welch’s t test, t 5 5.22,P< 0.05). There is a gradual shift in a positive directionin the fistula incidence in the STL group on cumulativemeta-analysis (Fig. 3C). This may reflect publicationbias, or may be explained by studies with smaller Ncoming from centers with less experience in operatingon salvage cases; therefore, it may reflect a true effect ofoperative experience on outcomes.

The meta-analyses presented in Figure 3 are basedon the fistula incidence after STL following radiotherapywith or without chemotherapy. To examine the influence

TABLE II.Quality Assessment Metric for Case Series.

1. Case series collected in more than 1 center (i.e., multicenterstudy)?

2. Is the hypothesis/aim/objective of the study clearly described?

3. Are the inclusion and exclusion criteria (case definition) clearlyreported?

4. Is there a clear definition of the outcomes reported?

5. Were data collected prospectively?

6. Is there an explicit statement that patients were recruitedconsecutively?

7. Are the main findings of the study clearly described?

8. Are outcomes stratified (e.g., by disease stage, abnormal testresults, and patient characteristics)?

Y 5 1, N 5 0, Min. 5 0, Max. 5 8.


1152

www.cebm.brown.edu/open_meta

TAB

LE

III.

Stu

dy-

Rela

ted

Co

variate

s.

Stu

dy

Year

Co

untr

yo

fO

rig

inS

ett

ing

%T

3/4

%P

art

ial

Phary

ng

ecto

my

Prim

ary

Surg

ery

(n)

Salv

ag

eS

urg

ery

(n)

CR

T(n

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ag

e)

RT

(n,

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fsalv

ag

e)

Co

ncurr

ent

CR

T(n

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of

CR

T)

Onla

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lap

s(t

yp

e,

N)

Qualit

yM

etr

ic(0

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Ikiz

et

al.

39

2000

Turk

ey

Tert

iary

refe

rral:

sin

gle

cente

r72

24

TL

(89)

TL

(3)

0(0

)3

(100)

––

5

Cavalo

tet

al.

17

2000

Italy

Tert

iary

refe

rral:

sin

gle

cente

r63

0T

L(2

65)

TL

(28)

0(0

)28

(100)

––

6

Herr

anz

et

al.

40

2000

Sp

ain

Tert

iary

refe

rral:

sin

gle

cente

r88

0T

L(4

25)

–0

(0)

0(0

)–

–6

Virta

nie

mi

et

al.4

12001

Fin

land

Tert

iary

refe

rral:

multic

ente

r58

0T

L(9

5)

TL

(38)

0(0

)38

(100)

––

7

Leo

net

al.

42

2001

Sp

ain

Tert

iary

refe

rral:

sin

gle

cente

r100

0–

TL

(24)

24

(100)

0(0

)0

(0)

–6

Gra

uet

al.4

32003

Denm

ark

Tert

iary

refe

rral:

multic

ente

r37

0–

TL

(472)

0(0

)472

(100)

––

7

Web

er

et

al.

42003

U.S

.A.

Tert

iary

refe

rral:

multic

ente

r87

0–

TL

(129)

75

(58)

54

(42)

27

(36)

–7

Sm

ith

et

al.

25

2003

Canad

aTe

rtia

ryre

ferr

al:

sin

gle

cente

r76

0T

L(1

68)

TL

(55)

0(0

)55

(100)

–P

MM

F(4

0)

5

Mark

ou

et

al.4

42004

Gre

ece

Tert

iary

refe

rral:

sin

gle

cente

r85

0T

L(2

91)

TL

(86)

0(0

)69

(80)

––

5

Galli

et

al.

45

2005

Italy

Tert

iary

refe

rral:

sin

gle

cente

r42

0T

L(1

90)

TL

(78)

0(0

)78

(100)

––

6

Ganle

yet

al.

12

2005

U.S

.A.

Tert

iary

refe

rral:

sin

gle

cente

r77

0T

L(1

13)

TL

(70)

38

(54)

32

(46)

15

(39)

–6

Rig

hin

iet

al.1

62005

Fra

nce

Tert

iary

refe

rral:

sin

gle

cente

r72

58

TL

(12)

TLP

P(2

2)

TL

(13)

TLP

P(1

3)

0(0

)60

(100)

–P

MM

F(2

6)

6

Makitie

et

al.

46

2006

Fin

land

Tert

iary

refe

rral:

sin

gle

cente

r–

0T

L(8

3)

TL

(25)

2(8

)23

(92)

0(0

)–

5

Mo

rto

net

al.4

72007

New Zeala

nd

Tert

iary

refe

rral:

sin

gle

cente

r–

32

TL/T

LP

P(8

4)

TL/T

LP

P(1

8)

0(0

)18

(100)

––

5

Ded

ivitis

et

al.

48

2007

Bra

zil

Tert

iary

refe

rral:

sin

gle

cente

r98

29

TL/T

LP

P(4

1)

TL/T

LP

P(1

4)

0(0

)14

(100)

––

5

Fung

et

al.1

92007

U.S

.A.

Tert

iary

refe

rral:

sin

gle

cente

r98

0–

TL

(41)

39

(95)

2(5

)39

(100)

RF

FF

(9)

ALT

(4)

Late

ral

Arm

(1)

6

Withro

wet

al.2

62007

U.S

.A.

Tert

iary

refe

rral:

multic

ente

r90

0–

TL

(20)

7(3

5)

13

(65)

7(1

00)

–6

Bo

sco

lo-R

izzo

et

al.1

42008

Italy

Tert

iary

refe

rral:

sin

gle

cente

r87

17

TL/T

LP

P(1

89)

TL/T

LP

P(2

9)

0(0

)189

(87)

––

6

Dirven

et

al.1

52009

Austr

alia

Tert

iary

refe

rral:

sin

gle

cente

r65

0T

L(5

7)

TL

(22)

6(2

7)

16

(73)

6(1

00)

–6

Gil

et

al.2

02009

U.S

.A.

Tert

iary

refe

rral:

sin

gle

cente

r60

0–

TL

(80)

24

(30)

56

(70)

24

(100)

PM

MF

(11)

6

Pate

l&

Keni2

42009

U.S

.A.

Tert

iary

refe

rral:

sin

gle

cente

r88

0T

L(2

6)

TL

(17)

11

(65)

6(3

5)

11

(100)

PM

MF

(10)

7

Relic

et

al.4

92009

Germ

any

Tert

iary

refe

rral:

sin

gle

cente

r93

0–

TL

(15)

15

(100)

0(0

)0

(0)

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TAB

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III.

(Co

ntinued

)

Stu

dy

Year

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2009

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The

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en

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32012

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10

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52

2012

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an

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37

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19

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53

2012

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54

2012

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4

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55

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39

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16

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56

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28

2013

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69

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rral:

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15

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32

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15

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ral

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ecto

my.

of chemotherapy on fistula incidence, subgroup analysescomparing fistula incidence in STL following radiother-apy alone with that in STL following chemoradiotherapy

were performed. The overall post-STL with primary clo-sure fistula incidence is 22.8% (18.3–27.4) followingradiotherapy alone (Fig. 4A), and 34.1% (22.6–45.6)

Fig. 2. Forest plots: Primary total laryngectomy, no flap. A) Random effects meta-analysis of proportions. Grey diamond and dashed lineindicates the summary overall estimate of fistula incidence, with 95% confidence intervals. The size of the squares is proportional to theweight applied to that study in the random effects model. B) Random effects leave-one-out meta-analysis (meta-influence plot). C) Randomeffects cumulative meta-analysis with studies ordered by decreasing N.B–C: Grey dashed line indicates the overall estimate as in A.


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following prior chemoradiotherapy (Fig. 5A, includesdata from both induction chemotherapy and concurrentchemoradiotherapy patients). STL following chemoradio-therapy is associated with a significantly higher risk of

fistula compared to PTL (Welch’s t test, t 5 3.29,P< 0.05), but not compared to STL following radiother-apy alone (Welch’s t test, t 5 1.79, P >0.05), despite atrend toward higher fistula incidence in the

Fig. 3. Forest plots: Salvage totallaryngectomy following radiotherapywith or without chemotherapy, noflap. A) Random effects meta-analysis of proportions. Grey dia-mond and dashed line indicates thesummary overall estimate of fistulaincidence, with 95% confidenceintervals. The size of the squares isproportional to the weight appliedto that study in the random effectsmodel. B) Random effects leave-one-out meta-analysis (meta-influ-ence plot). C) Random effectscumulative meta-analysis with stud-ies ordered by decreasing N.B–C: Grey dashed line indicates theoverall estimate as in A.


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chemoradiotherapy group. Similarly, there is a signifi-cant increase in fistula incidence for STL following priorradiotherapy alone compared to PTL (Welch’s t test,

t 5 3.14, P< 0.05). The cumulative meta-analysis forSTL following chemoradiotherapy shows a drift in theoverall estimate of fistula incidence from approximately

Fig. 4. Forest plots: Salvage total laryngectomy following radiotherapy, no flap. A) Random effects meta-analysis of proportions. Grey dia-mond and dashed line indicates the summary overall estimate of fistula incidence, with 95% confidence intervals. The size of the squaresis proportional to the weight applied to that study in the random effects model. B) Random effects leave-one-out meta-analysis (meta-influ-ence plot). C) Random effects cumulative meta-analysis with studies ordered by decreasing N.B–C: Grey dashed line indicates the overall estimate as in A.


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26%, with the five largest studies to 34.1% with theaddition of two smaller studies (Fig. 5C). This may indi-cate publication bias or a true effect of caseload onoutcome.

Effect of Prophylactic Vascularized Tissue FlapsThe overall fistula incidence in patients receiving a

vascularized tissue flap to reinforce the pharyngealsuture line following primary pharyngeal closure afterSTL is 10.3% (4.6–15.9) (Fig. 6A). In total, 24 of 188 STLpatients receiving a prophylactic flap developed a fistula.This is significantly lower than the incidence in patientsundergoing STL without a flap (27.6% [23.4–31.8];Welch’s t test, t 5 4.84, P< 0.05), but not significantly dif-ferent from patients undergoing PTL as their initialtreatment (14.3% [11.7–17.0]; Welch’s t test, t 5 1.26,P>0.05). No single study dominates the overall estimatein the “with flap” group (Fig. 6B). There is no evidencefor a systematic drift in the estimate with the addition ofsmall studies in the cumulative meta-analysis (Fig. 6C).

Analysis of data from studies reporting fistula inci-dence in patients receiving prophylactic flaps and a con-trol group of patients with no flap allows estimation ofthe relative risk (RR) of fistula formation in the presence

of a flap (Fig. 7A). The RR of a fistula with a prophylac-tic flap versus primary closure alone in STL is 0.566(0.374–0.856, P 5 0.001). There is no significant hetero-geneity between the studies, despite the use of severaldifferent tissue flaps, including both regional and freetissue transfer (Q 5 6.19, df 5 6, P 5 0.402, I2 5 3%).Based on 23 fistulae in 155 patients in the flap group,and 96 fistulae in 306 patients in the no flap group, theNNT to prevent one fistula is 6.05.

Assessment for Potential Publication BiasFigure 8 shows funnel plots for each of the meta-

analyses presented. Egger’s test was used to assess forasymmetry in these plots. Asymmetry can result fromseveral causes, only one of which is publication bias.There is significant asymmetry in Figure 8A (P<0.05),indicating potential publication bias in the primary totallaryngectomy data. One study (Cavalot et al., 2000)17 isoutside the lower 98% confidence interval, and another(Herranz et al., 2000)40 is outside the upper 98% confi-dence interval. There is also significant asymmetry inFigure 8B. This may indicate publication bias, althoughit may also represent a real effect of smaller studies insmaller centers experiencing higher complication rates

Fig. 5. Forest plots: Salvage total laryngectomy following radiotherapy with chemotherapy, no flap. A) Random effects meta-analysis of pro-portions. Grey diamond and dashed line indicates the summary overall estimate of fistula incidence, with 95% confidence intervals. Thesize of the squares is proportional to the weight applied to that study in the random effects model. B) Random effects leave-one-out meta-analysis (meta-influence plot). C) Random effects cumulative meta-analysis with studies ordered by decreasing N.B–C: Grey dashed line indicates the overall estimate as in A.


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than academic centers with higher volumes of STL cases.In contrast, Egger’s statistic suggests no asymmetry inthe analysis of STL patients with a flap (P>0.05, Fig.8C). In both subgroup analyses of the STL cases with noflap (radiotherapy alone; chemoradiotherapy) there is sig-nificant asymmetry (P< 0.05, Figs. 8D and 8E). However,caution should be applied in interpreting Egger’s statisticin the presence of significant heterogeneity.36

Heterogeneity of Effect and Meta-RegressionAnalyses

There is significant heterogeneity in the data for allmeta-analyses of STL cases with no flap (I2 5 71%, 60%,69% for chemoradiotherapy and radiotherapy combined,radiotherapy alone, and chemoradiotherapy alone groups,respectively). Random effects meta-regression analysis

with the covariates “% chemoradiotherapy,” “% concurrentchemoradiotherapy,” “% partial pharyngectomy,” “% T3/4disease,” “U.S.A.-based vs. non-U.S.A. based data,” “Singlecenter vs. multicenter,” and “quality score” (Table III) didnot reveal any significant independently associated covari-ate in the combined chemoradiotherapy and radiotherapyalone group, or any significant independent association ofconcurrent chemoradiotherapy with increased fistula inci-dence compared to induction chemotherapy. The heteroge-neity therefore cannot be explained by these factors.

DISCUSSION

Salvage Versus. Primary Total LaryngectomyRadiotherapy has long been associated with higher

postlaryngectomy fistula incidence compared to PTL.13,58

Fig. 6. Forest plots: Salvage total laryngectomy following radiotherapy with or without chemotherapy, with prophylactic “onlay” flap. A) Ran-dom effects meta-analysis of proportions. Grey diamond and dashed line indicates the summary overall estimate of fistula incidence, with95% confidence intervals. The size of the squares is proportional to the weight applied to that study in the random effects model. B) Ran-dom effects leave-one-out meta-analysis (meta-influence plot). C) Random effects cumulative meta-analysis with studies ordered bydecreasing N.B–C: Grey dashed line indicates the overall estimate as in A.


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The emergence of chemoradiotherapy protocols forlocally advanced laryngeal cancer has heightened con-cern regarding postoperative wound complications inthose patients requiring surgical salvage for residual orrecurrent disease,4,11,59 or for laryngopharyngeal dys-function.11,60,61 From the meta-analyses, it appears thatchemoradiotherapy increases the risk of major woundcomplications more than does radiotherapy alone. Theoutcomes of surgical salvage in the RTOG-91-11 trialcohort showed similar trends in fistula incidencebetween therapeutic groups; however, the differenceswere nonsignificant.4 Meta-analysis is a powerful toolallowing statistical examination of this effect in a largersample of patients across studies. There is, however, arisk of selection bias in the included observational stud-ies due their small size and often retrospective nature. Afurther limitation is the inclusion of both induction andconcurrent chemotherapy protocols because of insepara-bility of data. Compared to induction chemotherapy, con-current chemoradiotherapy protocols offer superiorlocoregional control at the expense of more frequentwound complications in the event of salvage surgery.4,62

Therefore, the estimate of postsalvage fistula incidencein the chemoradiotherapy group in this meta-analysislikely underestimates that expected in modern concur-rent chemoradiotherapy-based practice.

Effect of “Onlay” Flap-Reinforced PharyngealClosure

A prophylactic flap reinforcing the pharyngealsuture line in STL significantly reduces fistula incidence.The resulting fistula incidence in the flap patient groupis not significantly different from that in a contemporarysample of reports on PTL. Although it is not possible toextract data for fistula incidence in the flap-reinforcedprimary closure groups and primary closure alone groupsseparately for patients treated with prior radiotherapyalone and those receiving chemoradiotherapy as their ini-tial treatment, the data support the use prophylactic flapspreferentially in chemoradiotherapy survivors requiringTL. The effect of chemoradiotherapy on fistula incidenceis greater than radiotherapy alone but does not reach sta-tistical significance. Chemoradiotherapy patients are

Fig. 7. Forest plots: Salvage total laryngectomy following radiotherapy with or without chemotherapy, flap vs. no flap. A) Random effectsmeta-analysis of relative risk. Grey diamond and dashed line indicates the summary overall estimate, with 95% confidence intervals. Thesize of the squares is proportional to the weight applied to that study in the random effects model. B) Random effects leave-one-out meta-analysis (meta-influence plot). C) Random effects cumulative meta-analysis with studies ordered by decreasing N.B–C: Grey dashed line indicates the overall estimate as in A.A–C: Black dashed line indicates a relative risk of 1.


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most likely to benefit from the positive effects of a pro-phylactic flap on postoperative wound healing. Any bene-fit of prophylactic flaps for radiotherapy patients is likelyto be smaller since the deleterious effect of radiationalone on wound healing is less than that of chemoradio-therapy. In the radiotherapy alone group, the NNT to pre-vent one fistula is likely higher than the 6.05 quotedfrom the combined analysis. Conversely, the NNT is likelysmaller than this estimate for the chemoradiotherapygroup. In addition to an individual patient’s risk factorsand comorbid status, this will impact the weighing ofrisks and benefits of a prophylactic flap for each patientbeing counselled on salvage surgery.

Fistula SizeIt is important to consider the size and severity of a

fistula. Some are small, respond to conservative woundpacking and cessation of oral diet, and close spontane-ously in several days. Others are large, expose major ves-sels, require surgical closure, and risk carotid blowout ifleft untreated.11,13 No quantitative analysis of the effectof flaps on fistula size is possible due to inconsistency in

reporting between studies. However, several studies pro-vide evidence of a reduction in fistula size and the associ-ated morbidity and mortality in STL with a prophylacticflap compared to STL with primary closure alone.16,19,20

Righini et al.16 reported outcomes of postradiother-apy STL with or without an “onlay” pectoralis majormuscle flap (PMMF). Fistula incidence was lower in thePMMF group, but did not reach statistical significance.The authors noted that in the primary closure alonegroup there were two patients with fistulae which,despite attempts at surgical closure, never healed andwere ultimately fatal. Similarly, Gil et al.20 reported nosignificant difference in fistula incidence betweenPMMF-reinforced primary closure and primary closurealone groups in STL. However, 50% of fistulae in the pri-mary closure alone group required surgical closure at asecond procedure, compared to 0% in the PMMF group.

Mechanism of Flap-Associated Reduction inFistula Incidence

The rationale of placing prophylactic flaps into thewound to aid healing in the setting of previous

Fig. 8. Funnel plots. A) Primary total laryngectomy, no flap. B) Salvage total laryngectomy following radiotherapy with or without chemother-apy, no flap. C) Salvage total laryngectomy following radiotherapy with or without chemotherapy, with flap. D) Salvage total laryngectomyfollowing radiotherapy, no flap. E) Salvage total laryngectomy following radiotherapy with chemotherapy, no flap. A–E: Black dashed line-s 5 95% confidence intervals; black solid lines 5 98% confidence intervals; grey dashed lines 5 overall estimate from corresponding randomeffects meta-analysis.


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radiotherapy is based on the assumptions that hypoxiaresulting from the microvascular damage induced byradiation necessarily impairs wound healing, and there-fore predisposes to PCF formation, and that the additionof well-vascularized tissue can to some extent reversethis effect, perhaps through alteration of the local tissuemicroenvironment. Similar rationale is used to supportthe use of hyperbaric oxygen therapy and novel tissue-oxygenation enhancing compounds after surgery in otherpreviously irradiated sites.63,64 An alternative is that theflap simply offers mechanical support to the pharyngealsuture line. The precise mechanism(s) by which prophy-lactic flaps aid wound healing remains unknown.

Flap-Associated MorbidityStudies included in the meta-analysis employed sev-

eral different types of prophylactic vascularized tissueflap. The PMMF is the most common (151 of 188 cases).The advantages of this regional flap for head and neckreconstruction are its ease of harvest and relatively lowdonor-site morbidity. Some authors favor free tissuetransfer in the form of anterolateral thigh or radial fore-arm free flaps because of concern over morbidity associ-ated with the PMMF.19 Two important considerations inpatients previously treated with chemoradiotherapy arethe relative lack of useable vessels for microvascularanastomosis to allow free tissue transfer, and difficultydissecting the previously treated neck.11 Given a NNT of6.05 to prevent one fistula, it is important to weigh thepotential flap-associated morbidity against the potentialbenefit in these cases.

The lack of significant heterogeneity suggests thatthere is no difference in the effect of each type of flapused in an “onlay” technique. This is consistent with therationale that any nonirradiated vascularised tissue maybe beneficial in aiding wound healing. Therefore, thechoice of flap depends on patient factors, donor site mor-bidity, and the availability of technical expertise formicrovascular anastomosis. Despite a trend toward freetissue transfer in head and neck reconstruction, recentdata suggests no significant difference in morbiditybetween regional pedicled flaps and free flaps, and anacceptable short- and long-term morbidity profile for thePMMF.65,66

Limitations of the StudyWe performed meta-analyses on the outcomes of

retrospective observational studies of the PCF incidencefollowing laryngectomy. Some studies examined theeffect of a prophylactic flap on PCF incidence against acontrol group with no flap. There is evidence of possiblepublication bias in the included studies because theaddition of smaller studies to some cumulative meta-analyses resulted in a progressive drift toward higherPCF incidence. There are alternative explanations forthis drift, including a potential for higher complicationrates in less experienced centers when operating on com-plex salvage cases. Overall, the risk of bias is consider-able compared to a randomized controlled trial. We

focused only on PCF incidence. Flap-associated morbid-ity and the financial implications of the more complexreconstruction methods have not been assessed andshould be taken into account in future studies.

CONCLUSIONProphylactic tissue flaps placed over the pharyngeal

suture at the time of STL following failed organ-preservation protocols reduce the risk of PCF. Overallfistula incidence is 14.3% in PTL, 22.8% in STL follow-ing radiotherapy, 34.1% in STL following chemoradio-therapy, and only 10.3% in STL with an “onlay” flap.This reduction in fistula incidence prevents the associ-ated morbidity and mortality from exposed major vesselsin the neck. Chemoradiotherapy increases fistula inci-dence more than radiotherapy. Notwithstanding the lim-itations of the meta-analyses, prophylactic flaps arerecommended to aid pharyngeal closure in STL afterfailed chemo-radiotherapy. Prophylactic flaps may havea role after failed radiotherapy alone, but the benefitsmay be smaller in comparison to the failed chemo-radiotherapy group.

AcknowledgementsWe thank three anonymous reviewers for helpful com-ments on an earlier version of the article. No funding wassought in relation to this study.

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