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PDPDT 593 1

Photodiagnosis and Photodynamic Therapy (2014) xx , xxx–xxx

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jou rn al hom epage: www.elsev ier .com/ locate /pdpdt

HIGHLIGHTS

Photodiagnosis and Photodynamic Therapy xx (2014) xxx–xxxEfficacy of photodynamic therapy inthe management of oral premalig-nant lesions. A systematic review

Fahim Vohra, Abdulaziz A. Al-Kheraif, Talat Qadri, Mohamed Ibrahim Abu Hassan, Asma Ahmed,Saman Warnakulasuriya, Fawad Javed PhD, BDS∗

• Effect of PDT on oral leukoplakia, erythroplakia, erythro-leukoplakia and verrucous hyperplasia was assessed.• Overall, 13 studies were included in which numbers of patients ranged between 5 patients and 147 individuals.• Complete, partial and no response to PDT was shown by 27—100%, 5—50% and 0—25% of pre-malignant lesions,

respectively.• PDT is effective in the overall management of oral premalignant lesions.

PDPDT 593 1—10Please cite this article in press as: Vohra F, et al. Efficacy of photodynamic therapy in the manage-ment of oral premalignant lesions. A systematic review. Photodiagnosis and Photodynamic Therapy (2014),http://dx.doi.org/10.1016/j.pdpdt.2014.10.001

ARTICLE IN PRESS+ModelPDPDT 593 1—10

Photodiagnosis and Photodynamic Therapy (2014) xxx, xxx—xxx1

Available online at www.sciencedirect.com

ScienceDirect

journa l homepage: www.e lsev ier .com/ locate /pdpdt

REVIEW2

Efficacy of photodynamic therapy in themanagement of oral premalignant lesions. Asystematic review

3

4

5

Fahim Vohraa, Abdulaziz A. Al-Kheraifb, Talat Qadri c,Q1

Mohamed Ibrahim Abu Hassand, Asma Ahmede,f,Saman Warnakulasuriyag, Fawad Javed PhD, BDSh,∗

6

7

8

a Department of Prosthetic Dental Sciences, College of Dentistry, King Saud University, Riyadh, Saudi Arabia9

b Dental Biomaterials Research Chair, College of Applied Medical Sciences, King Saud University, Riyadh11541, Saudi Arabia

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11

c Division of Periodontology, Department of Dental Medicine, Karolinska Institute, Huddinge, Sweden12

d Department of Restorative Dentistry, Universiti Teknologi MARA, Shah Alam, Malaysia13

e Department of Laser Dentistry, RWTH Aachen University, Aachen, Germany14

f Department of Dentistry, Lifecare Hospital, Abu Dhabi, United Arab Emirates15

g Department of Oral Medicine, King’s College London and WHO Collaborating Centre for Oral Cancer andPrecancer, London, United Kingdom

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h Engineer Abdullah Bugshan Research Chair for Growth Factors and Bone Regeneration, 3D Imaging andBiomechanical Laboratory, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia

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19

Received 11 August 2014; received in revised form 26 September 2014; accepted 1 October 201420

KEYWORDSPhotodynamictherapy;Oral premalignantlesion;Leukoplakia;Erythroplakia;Erythro-leukoplakia;Verrucous hyperplasia

Summary1

Objective: The aim was to systematically review the efficacy of photodynamic therapy (PDT)in the management of oral premalignant lesions.

2

3

Methods: The addressed focused question was ‘‘Is PDT effective in the management of oralpremalignant lesions?’’ PubMed/Medline, Google-Scholar, EMBASE and ISI Web of Knowledgedatabases were searched from 1984 till June 2014 using different combinations of the followingkeywords: photodynamic therapy; oral premalignant lesions; leukoplakia; erythroplakia; ery-thro-leukoplakia; verrucous hyperplasia; and submucous fibrosis. Review articles, experimentalstudies, case-reports, commentaries, letters to the Editor, unpublished articles and articlespublished in languages other than English were not sought. The pattern of the present studywas customized to mainly summarize the relevant information.

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6

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∗ Corresponding author. Tel.: +966 50 968 6328; fax: +966 114698786.E-mail address: fawjav@gmail.com (F. Javed).

http://dx.doi.org/10.1016/j.pdpdt.2014.10.0011572-1000/© 2014 Elsevier B.V. All rights reserved.

PDPDT 593 1—10Please cite this article in press as: Vohra F, et al. Efficacy of photodynamic therapy in the manage-ment of oral premalignant lesions. A systematic review. Photodiagnosis and Photodynamic Therapy (2014),http://dx.doi.org/10.1016/j.pdpdt.2014.10.001

ARTICLE IN PRESS+ModelPDPDT 593 1—10

2 F. Vohra et al.

Results: Thirteen studies were included. In these studies, the number of patients rangedbetween 5 patients and 147 individuals with mean ages ranging between 51 years and 62.2 years.Oral premalignant lesions, which were investigated were leukoplakia, erythroplakia, erythro-leukoplakia and verrucous hyperplasia. Reported number of premalignant lesions ranged between5 and 225. Laser wavelength, duration of irradiation and power density were 585—660 nm,60 s to 16.6 min and 100—150 mW/cm2, respectively. Aminolevulinic acid, chlorine-e6, meta-tetrahydroxyphenylchlorin and photofrin were used as photosensitizer. The frequency of PDTapplication ranged between once and 12 times. Complete, partial and no response to PDT wasshown by 27—100%, 5—50% and 0—25% of pre-malignant lesions, respectively. The recurrence rateof pre-malignant lesions was up to 36%.

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29

30

Conclusion: PDT is effective in the overall management of oral premalignant lesions.31

© 2014 Elsevier B.V. All rights reserved.32

33

Contents1

Introduction............................................................................................................... 002

Materials and methods .................................................................................................... 003

Focused question..................................................................................................... 004

Eligibility criteria..................................................................................................... 005

Search strategy....................................................................................................... 006

Results .................................................................................................................... 007

General characteristics of the studies ................................................................................ 008

Laser related parameters of included studies......................................................................... 009

Photosensitizer related parameters of included studies............................................................... 0010

Outcomes of included studies ........................................................................................ 0011

Discussion ................................................................................................................. 0012

Recommendations......................................................................................................... 0013

Conclusion ................................................................................................................ 0014

Conflict of interest statement ............................................................................................. 0015

Acknowledgement....................................................................................................... 0016

Appendix A .............................................................................................................. 0017

References .............................................................................................................. 0018

Introduction19

A variety of therapeutic strategies have been proposed20

for the management of oral per-malignant lesions (such21

as leukoplakia [OL], oral erythroplakia [OE], oral ery-22

throleukoplakia [OEL], oral verrucous hyperplasia [OVH] and23

sub-mucous fibrosis). These treatment modalities include24

topical application of drugs (for example, vitamin A, antibi-25

otics and steroids) [1—4], laser ablation, cryotherapy and26

surgical excision [5,6]. Non-surgical management strategies27

(such as topical application of drugs) for the management of28

pre-malignant lesions may be successful in the short-term as29

high recurrence rates have been reported with this form of30

treatment [7,8]. Moreover, it has also been reported that31

surgical treatment of oral precancerous lesions increases32

morbidity and formation of scar tissue [9].33

Photodynamic therapy (PDT) is a contemporary treat-34

ment modality for the management of oral inflammatory35

conditions. PDT involves interaction between a light source36

and chemical dye or photosensitizer (PS) in the presence of37

oxygen [10,11]. This interaction produces reactive oxygen38

species [11,12] that cause oxidative damage to microbial39

cell walls and pre-malignant and malignant cells [13—15].40

In the study by Yu et al. [16], 35 patients with oral verru-41

cous hyperplasia (OVH) were treated using PDT. The results42

showed complete elimination of OVH with no recurrence up 43

to 35 months of follow up. Similar results were reported by 44

Chen et al. [15]. Results from these studies [15,16] suggest 45

that PDT is a potential therapeutic strategy for the manage- 46

ment of oral premalignant lesions. However, studies [17,18] 47

have also reported recurrence rates of up to 36% follow- 48

ing treatment of oral premalignant lesions using PDT. In this 49

regard, it seems that there is a controversy over the effec- 50

tiveness of PDT in the management of oral premalignant 51

lesions. To our knowledge from indexed literature, efficacy 52

of PDT in the management of oral premalignant lesions has 53

not been systematically reviewed. 54

The aim of the present study was to systematically review 55

the efficacy of PDT in the management of oral premalignant 56

lesions. 57

Materials and methods 58

Focused question 59

Based on the Preferred Reporting Items for Systematic 60

Reviews and Meta-Analyses (PRISMA) guidelines, a focused 61

question was constructed. The addressed focused question 62

was ‘‘Is PDT effective in the management of oral premalig- 63

nant lesions?’’ 64

PDPDT 593 1—10Please cite this article in press as: Vohra F, et al. Efficacy of photodynamic therapy in the manage-ment of oral premalignant lesions. A systematic review. Photodiagnosis and Photodynamic Therapy (2014),http://dx.doi.org/10.1016/j.pdpdt.2014.10.001

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PDT in the treatment of oral pre-malignant lesions 3

Records iden�fied through database searching

(n = 36)

Scre

enin

g In

clud

ed

Elig

ibili

ty

Iden

�fica

�on

Records a�er duplicates removed (n = 36)

Records screened (n = 36)

Records excluded with reasons (n = 23)

Full-text ar�cles assessed for eligibility

(n = 13)

Studies included in qualita�ve synthesis

(n = 13 )

Studies included in quan�ta�ve synthesis

(n = 13)

Fig. 1 Literature search according to the PRISMA guidelines(www.prisma-statement.org).

Eligibility criteria65

The following eligibility criteria were entailed: (a) original66

studies; (b) clinical studies; (c) intervention: efficacy of PDT67

in management of oral premalignant lesions; (d) articles68

published only in English language. Review articles, experi-69

mental studies, case-reports, commentaries, letters to the70

Editor and unpublished articles were excluded.71

Search strategy72

PubMed/Medline (National Library of Medicine, Bethesda,73

Maryland), Google-Scholar, EMBASE and ISI Web of Knowl-74

edge databases were searched from 1984 till June 2014 using75

different combinations of the following keywords: photo-76

dynamic therapy; oral premalignant lesions; leukoplakia;77

erythroplakia; erythroleukoplakia; verrucous hyperplasia;78

and submucous fibrosis. Titles and abstracts of studies that79

fulfilled the eligibility criteria were assessed by the authors80

(FV and FJ) and checked for agreement. Full-texts of rel-81

evant studies judged by title and abstract were read and82

independently assessed with reference to the eligibility83

criteria. Following this, reference lists of original and review84

studies that were found to be pertinent in the previous step85

were hand-searched and checked for agreement via discus-86

sion among the authors (Figure 1).87

The initial search yielded 36 studies. Twenty-three stud-88

ies, which did not fulfill the eligibility criteria, were89

excluded (Appendix A). In total, 13 studies [9,15—26] were90

included and processed for data extraction. The pattern of91

the present study was customized to mainly summarize the92

relevant information.93

Results 94

General characteristics of the studies 95

All studies [9,15—26] were clinical, had a prospective design 96

and were performed either at universities or healthcare cen- 97

ters. In these studies [9,15—26], patients histopathologically 98

diagnosed with pre-existing oral premalignant lesions with 99

or without dysplasia, were included. The total number of 100

subjects ranged between 5 patients and 147 individuals. 101

Seven studies [9,15,16,20—23] reported the mean age of 102

study participants, which was between 51 years and 62.2 103

years (age range 30—98 years). Nine studies [9,15,16,18—23] 104

reported the gender of subjects, in which the number of 105

female participants ranged between 0 and 65 individuals. 106

In all studies [9,15—26], premalignant lesions exposed 107

to treatment included OL, OE, OEL and OVH. The total 108

number of premalignant lesions reported in these studies 109

[9,15—26], ranged between 5 and 225 lesions. Twelve studies 110

[9,15—24,26] reported the site of lesions, which included, 111

buccal and labial mucosa (maxilla and mandible), tongue, 112

palate, floor of the mouth, bucco-gingival sulcus, retromo- 113

lar area, maxillary tuberosity and upper and lower alveolus 114

(Table 1). 115

In 12 [9,15—17,19—26] out of 13 studies [9,15—26], 116

PDT was used as the sole therapeutic strategy for the 117

management of oral premalignant lesions. In the study 118

by Kawczyk-Krupka et al. [18], efficacy of PDT was com- 119

pared with that of cryosurgery (control group) in the 120

management of oral premalignant lesions. The postopera- 121

tive follow up period ranged from 5 months up to 7.3 years 122

(Table 1). 123

In 9 studies [15—20,22—24], smokers (ranging between 124

5 and 87 individuals) were included. Two studies [19,20] 125

reported the frequency of smoking. In the study by Jerjes 126

et al. [20], 49 individuals smoked less than 20 daily and 38 127

patients smoked more than 20 cigarettes per day. In the 128

study by Pietruska et al. [19], all smokers (n = 6) smoked 129

less than 10 cigarettes daily. In four studies [15,16,22,23] 130

habitual areca-nut chewers were included, which ranged 131

between 5 individuals and 44 individuals. In the study by 132

Jerjes et al. [20], 65 individuals were habitual alcohol 133

users. 134

Laser related parameters of included studies 135

Diode lasers, light emitting diode (LED) and dye lasers 136

were used in four [19—22], four [15,16,22,23] and six 137

[9,17,18,24—26] studies, respectively. In the studies using 138

dye laser [9,17,18,24—26], pulsed dye laser, pumped dye 139

laser and argon pumped dye laser was used in, one [9], 140

one [26] and four [17,18,24,25] studies, respectively. In all 141

studies [9,15—26], lasers with wavelength, energy fluence 142

and power density ranging between 585 and 660 nanometers 143

(nm), 6 and 200 joules per square centimeters (J/cm2) and 144

100 and 150 milliwatts per square centimeters (mW/cm2), 145

respectively were used (Table 2). Laser power output was 146

reported by two studies [19,25], which were 300 mW (milli- 147

watts) and 800 mW, respectively. Duration of irradiation was 148

reported by eight studies [9,15—17,21—24], which ranged 149

between 60 s and 16.6 min. 150

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oforal

premalignant

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systematic

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Table 1 Characteristics of the studies included.

Authors Patients Mean age inyears(range)

Gender(female)

Treatmentprotocol

Pre-malignant lesion Followup

Study outcome(% of lesions)

Recurrence (%of patient)

Type Site Number (n)

Pietruska et al.[19]

23 NA (21—79) 16 All patientsweretreated withPDT.

OL BM, L, Gand T

44 Up to 5weeks

- 27.27%completeresponse- 50% partialresponse- 22% noresponse

NA

Kawczyk-Krupka et al.[18]

85 Group 1: NA(32—75)Group 2: NA(21—73)

48 Group 1: OLtreated withPDTGroup 2: OLtreated withcryosurgery

OL BM, MbM,MM, L, FM,P, T and B-Gsulcus

Group 1: 81Group 2: 72

Up to 34months

Group 1:- 78%completeresponse- 12.8%partialresponse- 9% noresponseGroup 2:- 89.2%completeresponse

Group 1: 27%Group 2: 24%

Jerjes et al.[20]

147 53 (41—98) 65 All patientsweretreated withPDT

OL and OE. T, BM, P,FM,RMA, TB,UA, LA

225 7.3 years - 81%completeresponse- 8.2% partialresponseb

- 11% noprogressivec orstable disease

19%

Shafirsteinet al. [9]

23 62.2(37—79)

11 OL lesionstreated withPDT

OL BM, RMA, T,P, A, FM andB-G sulcus.

27 Up to 3months

- 37%completeresponsea

- 48.1%partialresponse- 14.8% noresponse

4%

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F,et

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oforal

premalignant

lesions.A

systematic

review.

Photodiagnosisand

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Therapy(2014),

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Table 1 (Continued)

Authors Patients Mean age inyears(range)

Gender(female)

Treatmentprotocol

Pre-malignant lesion Followup

Study outcome(% of lesions)

Recurrence (%of patient)

Type Site Number (n)

Lin et al. [21] 80 Group 1: 50(42—74)Group 2: 58(34—89)

3 Group 1:OVH treatedwith PDTGroup 2:OEL treatedwith PDT

OVH andOEL

BM,T,L,A,P,FM

Group 1: 40Group 2: 40

Up to 37months

Group 1:- 100%completeresponseGroup 2:- 95%completeresponse- 5% partialresponse

Group1: NoneGroup 2: 21%

Yu et al. [22] 46 56 (34—89) 2 Group 1:OEL treatedwithALA + LEDGroup 2:OEL treatedwith ALA+laser

OEL BM,T, L,A,G, P,FM

Group 1:20Group 2: 26

Up to 72months

Group 1:- 85%completeresponse- 15% partialresponseGroup 2:- 96%completeresponse- 4% partialresponse

Group 1: 29%Group 2: 20%

Yu et al. [16] 36 51 (32—79) 1 OVHpatientsweretreated withPDT

OVH BM, L, A andP

36 Up to 35months

- 100%completeresponse

0%

Chen et al. [23] 32 Group 1: 50(32—61)Group 2: 54(30—73)

2 Group 1:OVH treatedwith PDTGroup 2: OLtreated withPDT

OVH and OL BM, L, T andLA

Group 1: 8Group 2: 24

Up to 14months

Group 1:- 100%completeresponseGroup 2:- 33%completeresponse- 66% partialresponse

Group1: 0%Group 2: 25%

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F,et

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inthe

manage-

ment

oforal

premalignant

lesions.A

systematic

review.

Photodiagnosisand

Photodynamic

Therapy(2014),

http://dx.doi.org/10.1016/j.pdpdt.2014.10.001

AR

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Table 1 (Continued)

Authors Patients Mean age inyears(range)

Gender(female)

Treatmentprotocol

Pre-malignant lesion Follow up Study outcome(% of lesions)

Recurrence (%of patient)

Type Site Number (n)

Chen et al. [15] 5 52 (37—64) 0 OVHpatientsweretreated withPDT

OVH BM and L 5 Up to 11months

- 100%completeresponse

0%

Sieron et al.[24]

12 NA (32—70) NA OL patientstreated withPDT

OL BM, FM, L,G,B-G sulcusand MbM.

24 Up to 34months

- 83.33%completeresponse- 12.5% partialresponse- 4.1% noresponse

10%

Sieron et al.[25]

5 NA NA OL patientstreated withPDT

OL NA 12 6 months - 80%completeresponse- 20% partialresponse

20%

Kubler et al.[17]

12 NA NA OL patientstreated withPDT

OL BM, FM andB-G sulcus

12 Up to 16months

- 41.6%completeresponse- 33.33%partial response- 25% noresponse

NA

Grant et al. [26] 11 NA NA Patientswith OL,OEL and OEtreated withPDT

OL, OEL andOE

BM, T, L, Aand FM

21 Up to 19months

- 90.4%,completeresponse- 9.5%, partialresponse

36%

PDT: photodynamic therapy; OL: oral leukoplakia; OE: oral erythroplakia; OEL: oral erythro-leukoplakia; BM: buccal mucosa; MbM: mandibular mucosa; MM: maxillary mucosa; L:lips; FM: floor of the mouth; P: palate; T: tongue; B-G sulcus: bucco-gingival sulcus; RMA: retro-molar area; TB: tuberosity; U: upper; A: alveolus; L: lower alveolus; mTHPC: meta-tetrahydroxyphenylchlorin; ALA: aminolevulinic acid; HTP: histopathology; IHC: immune-histo-chemistry; OVH: oral verrucous hyperplasia.LED: light emitting diode; partial response: At least 20—25% lesion regression; complete response: absence of lesion on inspection; no response: lesion reduction by less then 20—25%.

a Complete response: more than 75% of lesion regression.b 30% decrease in the sum of the longest diameter of target lesions.c At least 20% increase in the sum of LD of target lesions.

PDPDT 593 1—10Please cite this article in press as: Vohra F, et al. Efficacy of photodynamic therapy in the manage-ment of oral premalignant lesions. A systematic review. Photodiagnosis and Photodynamic Therapy (2014),http://dx.doi.org/10.1016/j.pdpdt.2014.10.001

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PDT in the treatment of oral pre-malignant lesions 7

Table 2 Laser parameters of studies that fulfilled our eligibility criteria.

Authors Source Wavelength(in nm)

Energyfluence (inJ/cm2)

Poweroutput (inmW)

Powerdensity (inmW/cm2)

Duration ofirradiation(in s)

Pietruska et al. [19] Diode laser 660 90 300 NA NAKawczyk-Krupka

et al. [18]Dye laser 630—635 100 NA NA NA

Jerjes et al. [20] Diode laser Group 1:628Group 2:652

Group 1:100—200Group 2: 20

NA NA NA

Shafirstein et al. [9] Dye laser 585 6—8 NA NA 60—180Lin et al. [21] Diode laser 635 100 NA 100 1000Yu et al. [22] LED (red)

Diode laser635 NA NA 100 1000

Yu et al. [16] LED (red) 635 100 NA 100 1000Chen et al. [23] LED (red) 635 100 NA 100 1000Chen et al. [15] LED 635 100 NA 100 1000Sieron et al. [24] Dye laser 635 100 NA 150 900Sieron et al. [25] Dye laser 635 200 800 NA NAKubler et al. [17] Dye laser 635 100 NA 100 1000Grant et al. [26] Dye laser 630 50—100 NA 150 NA

J/cm2: Joules per square centimeters; nm: nanometers; mW: milliwatts; mW/cm2: milliwatts per square centimeters; LED: light emittingdiode.

Photosensitizer related parameters of included151

studies152

In 11 studies [9,15—18,20—25], aminolevulinic acid (ALA)153

(10—20%) was used as PS. Chlorine-e6 (20%), meta-154

tetrahydroxyphenylchlorin (mTHPC) (0.1 mg/kg) and155

photofrin (2 mg/kg) were used as PS in the studies by156

Pietruska et al. [19], Jerjes et al. [20] and Grant et al.157

[26], respectively. In 12 studies [9,15—25], PS was applied158

topically in the form of emulsion, gel or cream. Intra-lesion159

and intravenous administration of PS was performed in one160

[9] and two studies [20,26], respectively. Eleven studies161

[9,15,16,18—25], reported the frequency of PDT applica-162

tion, which ranged from one to twelve times throughout163

the study period. In studies using topical and intra-lesion164

application of PS [9,15—25], the pre-irradiation time165

ranged from 60 min to 300 min. In the studies by Jerjes166

et al. [20] and Grant et al. [26], pre-irradiation time167

for intravenous administration of PS was 96 h and 48 h,168

respectively (Table 3).169

Outcomes of included studies170

In all studies [9,15—26], the outcomes of oral premalignant171

lesions following PDT were categorized as complete, par-172

tial and no response. In these studies [9,15—26], 27—100%173

of premalignant lesions showed complete response to174

PDT; however, partial response was reported in 5—50% of175

pre-malignant lesions. In six studies [9,17—20,24], pre-176

malignant lesions ranging from 0% to 25% showed no response177

to PDT. Eleven studies [9,15,16,18,20—26], reported the178

recurrence rate of premalignant lesions in patients treated179

with PDT and it ranged between 0% and 36%.180

Discussion 181

In the present study, we reviewed the pertinent litera- 182

ture regarding the efficacy of PDT in the management of 183

oral pre malignant lesions. In nearly 30% studies [15,21—23] 184

pre-malignant lesions resolved completely following PDT. 185

However, it is pertinent to mention that complete resolu- 186

tion occurred only for specific types of lesions (and not all 187

the lesions treated by PDT). For example, in the study by 188

Lin et al. [21], OVH and OEL were treated by PDT; how- 189

ever only OVH showed 100% resolution with no recurrence 190

up to 37 months of follow up. Similarly, in the study by Chen 191

et al. [23] only cases in group 1 (OVH lesions) responded 192

completely to PDT whereas lesions of OL showed a partial 193

response to the same treatment protocol. The verrucous sur- 194

face of OVH lesions provides an increased surface area for 195

application of PS, thereby enhancing the overall effect of 196

PDT [16]. In addition, dysplastic oral premalignant lesions 197

have thinner surface keratin, increased epithelial perme- 198

ability and accelerated epithelial cell division [21]. These 199

features allow improved diffusion and retention of PS and 200

destruction of cells by PDT [21]. Likewise, size of the lesion 201

is also a critical factor that influences the efficacy of PDT 202

[21]. It is possible that OL lesions treated by PDT in the study 203

by Shafirstein et al. [9] were smaller in size than those in the 204

study by Kawczyk Krupka et al. [18]. This may be an expla- 205

nation for the reduced recurrence of lesion in the study by 206

Shafirstein et al. [9] as compared to the results reported 207

by Kawczyk Krupka et al. [18]. It is however noteworthy 208

that nearly 69% studies [9,15,17,18,20,23—26] included in 209

the present review did not draw a relationship between the 210

size and appearance of the lesion and their outcome after 211

PDT. For example, in the study by Yu et al. [16] clinical 212

outcomes of 36 OVH lesions were assessed following PDT. 213

PDPDT 593 1—10Please cite this article in press as: Vohra F, et al. Efficacy of photodynamic therapy in the manage-ment of oral premalignant lesions. A systematic review. Photodiagnosis and Photodynamic Therapy (2014),http://dx.doi.org/10.1016/j.pdpdt.2014.10.001

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8 F. Vohra et al.

Table 3 Characteristics of photosensitizers used in studies that fulfilled our eligibility criteria.Q2

Authors Route ofadministration

Frequency ofPDT

Type of PS Pre-irradiationtime (min)

Concentration/sof PS used

Pietruska et al. [19] Topical 10 times Chlorine-e6 60 20%Kawczyk-Krupka

et al. [18]Topical 2—12 times ALA 120 10% and 20%

Jerjes et al. [20] Group 1:TopicalGroup 2: IVinjection

At least once Group 1: ALAGroup 2:mTHPC

Group 1:180—240Group 2: 5760

ALA 60 mg/kgmTHPC0.1 mg/kg

Shafirstein et al. [9] Topical and ILinjection

1—2 times ALA 90 20%

Lin et al. [21] Topical 2—8 ALA 90—120 20%Yu et al. [22] Topical 2—7 ALA 90—120 20%Yu et al. [16] Topical 8 ALA 90—120 20%Chen et al. [23] Topical 8 ALA 120 20%Chen et al. [15] Topical 3 ALA 90—120 20%Sieron et al. [24] Topical Up to 8 ALA 240 10%Sieron et al. [25] Topical 1—5 ALA 240—300 10%Kubler et al. [17] Topical NA ALA 120 20%Grant et al. [26] IV NA Photofrin 2880 2 mg/kg

PS: photosensitizer; ALA: aminolevulinic acid; mTHPC: meta-tetrahydroxyphenylchlorin; IV: intravenous; IL: intralesion.BM: buccal mucosa; MbM: mandibular mucosa; MM: maxillary mucosa; L: lips; FM: floor of the mouth; P: palate; T: tongue; B-G sulcus:bucco-gingival sulcus; RMA: retro-molar area; TB: tuberosity; UA: upper alveolus; LA: lower alveolus.*PDT for OVH was once/week and PDT for OL was twice/week.PDT was done once/week.

It was concluded that premalignant lesions of less than or214

equal to 3.1 cm required fewer PDT applications as com-215

pared to those with greater size. This suggests that the216

efficacy of PDT in the management of oral premalignant217

lesions is dependent on the various factors including dys-218

plasia, type, size and surface characteristics of the lesion219

[15,16,19,21]. Further studies focusing on the efficacy of220

PDT in the management of oral pre malignant lesions with221

particular emphasis on size of the lesion are warranted.222

We observed that the frequency and duration of PDT223

varied amongst the studies included in the present review224

[9,15—26]. For example, Kawczyk Krupka et al. [18] per-225

formed PDT up to 12 times using ALA on OL lesions and226

observed a recurrence in 27% cases; whereas, in the study227

by Shafirstein et al. [9] PDT was performed on OL lesions228

up to twice throughout the study period with recurrences229

in 4% cases. Therefore, it seems that there is a lack of230

consensus over the precise duration and frequency of PDT231

that would help completely eliminate oral premalignant232

lesions and hence further studies are warranted in this233

regard.234

Studies [11,13,27—29] have reported that PDT is useful in235

the treatment of various oral inflammatory conditions such236

as periodontitis, peri-implantitis and endodontic infections;237

however, in these studies [11,13,27—29], PDT was always238

used as an adjunct to conventional therapeutic protocols239

(such as mechanical debridement of infected surfaces). It240

is worth mentioning that in nearly 92% studies included in241

the present review, PDT was used as a sole treatment strat-242

egy for the treatment of oral premalignant lesions. It is243

therefore hypothesized that treatment of oral premalignant244

lesions using PDT as an adjunct to other therapeutic regimes245

(such as topical vitamin A, antibiotic or steroid application 246

and laser ablation) is more effective in eradicating the lesion 247

and preventing recurrence as compared to when PDT is used 248

alone. Further prospective studies are warranted to test this 249

hypothesis. 250

It is well known that tobacco smoking and alcohol con- 251

sumption are significant risk factors for oral premalignant 252

and malignant lesions [30,31]. Smokers were included in 253

9 studies [15—20,22—24] and the recurrence rates of the 254

lesions following PDT in these studies ranged between 19% 255

and 27%. An explanation for this maybe that smokers, proba- 256

bly continued to smoke following PDT, thereby leading to the 257

recurrence of oral premalignant lesions in these individuals. 258

Likewise, in the study by Jerjes et al. [20], a recurrence rate 259

of 19% was reported. It is possible that the 65 habitual alco- 260

hol users included in this study [19] continued to consume 261

alcohol after PDT. 262

Recommendations 263

It is highly recommended that patients with oral inflamma- 264

tory/precancerous conditions undergoing treatment should 265

be discouraged from continuing tobacco and alcohol con- 266

sumption; and should also be educated about how using 267

tobacco products and alcohol may increase the risk of 268

oral cancer. Moreover, it has been reported that poor oral 269

hygiene status is a significant risk factor for oral prema- 270

lignant and malignant lesions [32]. Therefore, oral health 271

promotion efforts should also be emphasized in the com- 272

munity and among patients undergoing treatment for oral 273

precancer and cancer. 274

PDPDT 593 1—10Please cite this article in press as: Vohra F, et al. Efficacy of photodynamic therapy in the manage-ment of oral premalignant lesions. A systematic review. Photodiagnosis and Photodynamic Therapy (2014),http://dx.doi.org/10.1016/j.pdpdt.2014.10.001

ARTICLE IN PRESS+ModelPDPDT 593 1—10

PDT in the treatment of oral pre-malignant lesions 9

Conclusion275

PDT is a useful treatment strategy in the management of276

oral pre malignant lesions. However it is emphasized that277

other contributory factors such as size of the lesion, site of278

the lesion, dysplastic potential, consistency of lesion and279

tobacco/alcohol habits are significant factors that influence280

the overall success of PDT for the management of oral pre-281

malignant lesions.282

Conflict of interest statement283

None declared.284

Acknowledgement285

The authors would like to extend their appreciation to the286

research center, College of Applied Medical Sciences and287

Deanship of Scientific Research at King Saud University for288

funding this research.289

Appendix A.290

List of excluded studies. Reason for exclusion is shown in291

parenthesis.292

(a) Yu CH, Chen HM, Lin HP, Chiang CP. Expression of Bak293

and Bak/Mcl-1 ratio can predict photodynamic therapy294

outcome for oral verrucous hyperplasia and leuko-295

plakia. J Oral Pathol Med 2013;42:257—62. (Focused296

question not answered)297

(b) Chang YC, Yu CH. Successful treatment of oral verrucous298

hyperplasia with photodynamic therapy combined with299

cryotherapy — report of 3 cases. Photodiagn Photodyn300

Ther 2014;11:127—9. (Case report)301

(c) Sardella A, Carrassi A, Tarozzi M, Lodi G.302

Bisphosphonate-related osteonecrosis of the jaws303

associated with photodynamic therapy. J Oral Max-304

illofac Surg 2011;69:e314—6. (Focused question not305

answered)306

(d) Santos NR, Aciole GT, Marchionni AM, Soares LG,307

dos Santos JN, Pinheiro AL. A feasible procedure in308

dental practice: the treatment of oral dysplastic hyper-309

keratotic lesions of the oral cavity with the CO2310

laser. Photomed Laser Surg 2010;28 Suppl. 2:S121—6.311

(Focused question not answered)312

(e) Ribeiro AS, Salles PR, da Silva TA, Mesquita RA. A review313

of the nonsurgical treatment of oral leukoplakia. Int J314

Dent 2010;2010:186018. (Review)315

(f) Wang YP, Chen HM, Kuo RC, Yu CH, Sun A, Liu BY, et al.316

Oral verrucous hyperplasia: histologic classification,317

prognosis, and clinical implications. J Oral Pathol Med318

2009;38(8):651—6. (Focused question not answered)319

(g) Kvaal SI, Warloe T. Photodynamic treatment of oral320

lesions. J Environ Pathol Toxicol Oncol 2007;26:127—33.321

(Review)322

(h) Konopka K, Goslinski T. Photodynamic therapy in den-323

tistry. J Dent Res 2007;86:694—707. (Review)324

(i) Franco RA, Jr. Aminolevulinic acid 585 nm pulsed325

dye laser photodynamic treatment of laryngeal326

keratosis with atypia. Otolaryngol. — Head Neck Surg 327

2007;136:882—7. (Focused question not answered) 328

(j) Sadri M, McMahon J, Parker A. Management of laryn- 329

geal dysplasia: a review. Eur Arch Otorhinolaryngol 330

2006;263:843—52. (Review) 331

(k) Betz CS, Leunig A. Potential and limitations of fluo- 332

rescence diagnosis and photodynamic therapy. Part II. 333

Photodynamic therapy. HNO 2004;52:175—92. (Article 334

in German) 335

(l) Sudbo J, Warloe T, Aamdal S, Reith A, Bryne M. Diagnosis 336

and treatment of oral precancerous lesions. Tidsskrift 337

for den Norske Laegeforening 2001;121:3066—71. (Arti- 338

cle in Norwegian and Focused question not answered) 339

(m) Karrer S, Szeimies RM, Hohenleutner U, Landthaler 340

M. Role of lasers and photodynamic therapy in 341

the treatment of cutaneous malignancy. Am J 342

Clin Dermatol 2001;2:229—37. (Focused question not 343

answered) 344

(n) Leunig A, Betz CS, Baumgartner R, Grevers G, Iss- 345

ing WJ. Initial experience in the treatment of oral 346

leukoplakia with high-dose vitamin A and follow-up 347

5-aminolevulinic acid induced protoporphyrin IX fluo- 348

rescence. Eur Arch Otorhinolaryngol 2000;257:327—31. 349

(Focused question not answered) 350

(o) Malczewski M, Birecki J, Symonowicz K, Bronowicz A, 351

Ziolkowski P, Rabczynski J, et al. Clinical applications 352

of photodynamic therapy in the treatment of laryngeal 353

lesions. Otolaryngol Polska 1999;53:671—5. (Focused 354

question not answered) 355

(p) Sieron A, Namyslowski G, Misiolek M, Adamek M, 356

Kawczyk-Krupka A. Photodynamic therapy of prema- 357

lignant lesions and local recurrence of laryngeal and 358

hypopharyngeal cancers. Eur Arch Otorhinolaryngol 359

2001;258:349—52. (Focused question not answered) 360

(q) Zakrzewska JM, Lopes V, Speight P, Hopper C. Proli- 361

ferative verrucous leukoplakia: a report of ten cases. 362

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 363

1996;82:396—401. (Focused question not answered) 364

(r) Landthaler M, Szeimies RM, Hohenleutner U. Laser 365

therapy of skin tumors. Recent Results Cancer Res 366

1995;139:417—21. (Focused question not answered) 367

(s) Biel MA. Photodynamic therapy and the treatment 368

of neoplastic diseases of the larynx. Laryngoscope 369

1994;104:399—403. (Focused question not answered) 370

(t) Yu LF. Zhu-Hong-Jun ointment — a photosensitive sub- 371

stance for the treatment of white lesion of vulva. Zhong 372

hua Fu Chan Ke Za Zhi. 1984;19:29—31. (Focused ques- 373

tion not answered) 374

(u) Tsai JC, Chiang CP, Chen HM, Huang SB, Wang CW, Lee 375

MI, et al. Photodynamic therapy of oral dysplasia with 376

topical 5-aminolevulinic acid and light-emitting diode 377

array. Lasers Surg Med 2004;34:18—24. (Experimental 378

study) 379

(v) Wong SJ, Campbell B, Massey B, Lynch DP, Cohen 380

EE, Blair E, et al. A phase I trial of aminolevulinic 381

acid-photodynamic therapy for treatment of oral leuko- 382

plakia. Oral Oncol 2013;49:970—6. (Focused question 383

not answered) 384

(w) Kingsbury JS, Cecere W, Mang TS, Liebow C. Photody- 385

namic therapy for premalignant lesions in DMBA-treated 386

hamsters: a preliminary study. J Oral Maxillofac Surg 387

1997;55:376—81. (Experimental study). 388

PDPDT 593 1—10Please cite this article in press as: Vohra F, et al. Efficacy of photodynamic therapy in the manage-ment of oral premalignant lesions. A systematic review. Photodiagnosis and Photodynamic Therapy (2014),http://dx.doi.org/10.1016/j.pdpdt.2014.10.001

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