photodynamic therapy of non-melanoma skin cancers

ISSN 1054�660X, Laser Physics, 2011, Vol. 21, No. 2, pp. 427–433.© Pleiades Publishing, Ltd., 2011.Original Text © Astro, Ltd., 2011.

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1 INTRODUCTION

Non�melanoma skin cancers (NMSCs) incidencehas been steadily increasing worldwide at a rate of 3 to8% per year since 1964 [1] with greater increasesnearer the equator [2]. Pakistan is a developing agri�cultural country where approximately 70% populationlives in the rural areas. People living in the rural areasare actively involved in agricultural farming andaffected by ultraviolet radiations through sun expo�sure. This rural population is a most vulnerable groupfor the development of non�melanoma skin cancers(NMSCs) and their precursors. Furthermore, we arealso receiving a significant number of NMSC casesfrom Afghanistan having low level of healthcare facil�ities. Therefore, we need some new treatment modal�ities for the management of NMSCs which should behighly specific, non invasive, effective and safe. Pho�todynamic therapy (PDT) is an emerging treatmentmodality that involves the use of light to activate aphotosensitizer, localized in the diseased tissues,resulting in the formation of cytotoxic reactive oxygenspecies causing selective cellular death [3, 4].

1 The article is published in the original.

Topical photodynamic therapy is currently used forthe treatment of superficial non�melanoma skin can�cers (NMSCs) and their precursors such as actinickeratosis, Bowen’s disease, basal cell carcinoma,superficial as well as nodular and superficial Squa�mous Cell Carcinoma [5]. Topical PDT also has itspotential for use in the treatment of some non�onco�logical indications like acne vulgaris, psoriasis, photoaging, viral warts, and cutaneous T�cell Lymphoma[5, 6]. We have developed our well equipped, state ofthe art Biophotonics laboratory in 2007 for the firsttime in Pakistan where different clinical and basicresearch projects are in smooth progress. In this cur�rent study, we are interested to investigate the efficacy,safety and tolerability along with cosmetic outcome oftopical 5�aminolaevulinic acid photodynamic therapyfor the treatment of NMSCs and their precursors.

STUDY DESIGN. MATERIALS AND METHODS

Inclusion Criteria

In this study, we included patients of age 18 yearsand above, both sexes, suffering from NMSCs andtheir precursors including actinic keratosis, Bowen’s

LASER METHODS IN CHEMISTRY,BIOLOGY, AND MEDICINE

Photodynamic Therapy of Non�Melanoma Skin Cancers1

M. Ikrama, R. U. Khanb, S. Firdousc, and M. Atif c, *, and M. Nawazc

a Pakistan Institute of Engineering and Applied Sciences (PIEAS), Nilore, Islamabad, Pakistanb PAEC General Hospital, Sector H�11/4, Islamabad, Pakistan

c National Institute of Lasers and Optronics, Nilore, Islamabad, Pakistan*e�mail: [email protected]

Received August 24, 2010; in final form, September 6, 2010; published online December 23, 2010

Abstract—In this prospective study duly approved from Institutional Ethics Review Committee for researchin medicine, PAEC General Hospital Islamabad, Pakistan, we investigate the efficacy, safety and tolerabilityalong with cosmetic outcome of topical 5�aminolaevulinic acid photodynamic therapy for superficial non�melanoma skin cancers (NMSCs) and their precursors. Patients with Histological diagnosis of NMSCs andtheir precursors were assessed for PDT, after photographic documentation of the lesions and written consent,underwent two (2) sessions of PDT in one month (4 weeks) according to standard protocol. A freshly pre�pared 20% 5�ALA in Unguentum base was applied under occlusive dressing for 4–6 h as Drug Light Interval(DLI) and irradiated with light of 630 nm wavelength from a diode laser at standard dose of 90 J/cm2. Approx�imately 11% patients reported pain during treatment which was managed in different simple ways. In ourstudy we regularly followed up the patients for gross as well as histopathological response and recurrence freeperiods during median follow�up of 24 months. Regarding Basal cell carcinomas complete response wasobserved in 86.2% (25/29), partial response in 10.3% (3/29) and recurrence during first year in 3.5% (1/29)lesions. All the lesions which showed partial response or recurrence were nBCCs. Regarding Actinic Kerato�sis complete response was observed in 95.3% (20/21), partial response in 4.7% (1/21) while Bowen’s diseaseshowed 100% (2/2) results. 81.8% (9/11) Squamous Cell Carcinomas showed complete, 9% (1/11) partialresponse and 9% (1/11) presented with recurrence after 3 months. We observed excellent and good cosmeticresults along with tumor clearance in our study. Treatment sessions were well tolerated with high level ofpatient’s satisfaction and only minor side effects of pain during treatment sessions and inflammatory changespost photodynamic therapy were observed. We concluded that 5�ALA PDT is an effective and safe emergingtreatment modality for management of superficial non�melanoma skin cancers and their precursors with bet�ter cosmetic outcome and minor side effects.

DOI: 10.1134/S1054660X11030042

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IKRAM et al.

disease, superficial as well as nodular basal cell carci�noma and superficial squamous cell carcinoma.

Exclusion Criteria

We excluded patients having known hypersensitiv�ity to photosensitizer and/or light, pregnant ladies,Lactating mothers and children. We also excludedpatients suffering from Porphyrrhoea, Pigmented andmorphiec type of Basal Cell Carcinomas.

Ethical Issues

Study protocols were approved from InstitutionalReview Board/committee. Informed written consentwas taken from the patients. Research benefits weregiven to the patients. There was no conflict of interest.

Treatment Procedure

This study reports the treatment of 25 patients whohave given their informed written consent including14 males, 11 females with median age of 63 years(range 37–81). These 25 patients were having totalnumber of 63 lesions including 29 Basal cell carcino�mas (BCCs) 08 sBCCs while 09 nBCCs, 21 ActinicKeratoses (AKs), 02 Bowen’s diseases (BD), and 11squamous cell carcinomas (SCCs). Among these25 patients, 13 were having single NMSC whileremaining 12 having multiple lesions including fieldcancerization. In these 63 lesions, 51 were primary,never treated before while 12 recurrent ones previouslytreated with radiotherapy or surgery including10 BCCs & 02 SCCs. Patients with Histological diag�nosis of NMSCs and their precursors were assessed forPDT, and after photographic documentation of thelesions and informed written consent, they underwenttwo (2) sessions of 5�ALA PDT in four weeks accord�ing to standard protocol. First the lesion sites wereprepared with light curettage or gentle scrapping toremove crusts and scales without causing bleeding.Then a freshly prepared 20% 5�ALA in Unguentumbase was applied under occlusive dressing for 4–6 h asDrug Light Interval (DLI). After completion of DLI,dressing and residual 5�ALA was removed, site(s)viewed for gross tumor margins and fluorescence out�line to demarcate the irradiation field including a 5mm rim of clinically normal appearing tissue. Irradia�tion for a specific calculated time period was thencompleted with light of 630 nm wavelength in the formof continuous beam from a diode laser @ standarddose of 90 J/cm2. Patients reported pain of mild, mod�erate and severe intensity during treatment sessions.This pain was managed in different simple ways likechatting with the patient to divert attention, a coolingfan and in approximately 11% cases with severe pain,local xylocaine spray used. All patients observed 48 hpost PDT sun exposure avoidance for prevention ofphototoxicity. Post PDT phototoxicity was analyzed

on a scale of non/mild/moderate/severe. For patientswith complains of pain and itching after treatment ses�sions we advised Paracetamol (Acetaminophen) to getsymptomatic control. Patients were regularly followedup for treatment response, cosmetic outcome and sideeffects.

RESULTS

In our study we regularly followed up the patientsfor gross as well as histopathological response andrecurrence free periods during median follow up of24 months. Regarding Basal cell carcinomas completeresponse was observed in 86.2% (25/29), partialresponse in 10.3% (3/29) and recurrence during firstyear in 3.5% (1/29) lesions. All the lesions whichshowed partial response or recurrence were nBCCs.Regarding Actinic Keratosis complete response wasobserved in 95.3% (20/21), partial response in 4.7%(1/21) while Bowen’s disease showed 100% (2/2)results. 81.8% (9/11) Squamous Cell Carcinomasshowed complete, 9% (1/11) partial response and 9%(1/11) presented with recurrence after 3 months. Weobserved excellent and good cosmetic results alongwith tumor clearance in our study. Treatment sessionswere well tolerated with high level of patient’s satisfac�tion and only minor side effects of pain during treat�ment sessions and inflammatory changes post photo�dynamic therapy were observed.

DISCUSSION

Treatment of NMSCs with photodynamic therapyfor the first time in Pakistan was really an interestingand inevitable experience in which cancer patientswere treated without surgery, chemotherapy andradiotherapy. The results were encouraging, compara�ble with conventional therapies with some addedadvantages and highly appreciated by local and foreignexperts of the field. Photodynamic therapy is a highlyspecific, non invasive emerging technology used forthe treatment of NMSCs and some other non onco�logical conditions [5, 6]. The precise mechanisms atcellular level underlying the efficacy of topical PDT inthe treatment of NMSC are not fully known but bothapoptosis and necrosis have been described as occur�ring after topical PDT and the importance of eachphenomenon may be influenced by intracellular local�ization of the photosensitizer and illumination param�eters [3, 7–9]. In our study, we found that topical5�ALA PDT is a selective, tissue sparing, noninvasivetherapy with high efficacy, good tolerability, bettercosmetic outcome (as shown in Figs. 1–3) and lesserside effects particularly well suited for the treatment ofsuperficial lesions like Actinic Keratosis, Bowen’s dis�ease and sBCCs. Our patients showed completeresponse rates of 95.3, 100 and 86.2% for AKs, BD,and sBCCs, respectively (Fig. 4), which are compara�ble with latest available data in the literature for topical


PHOTODYNAMIC THERAPY OF NON�MELANOMA SKIN CANCERS 429

5�ALA PDT [10]. The above mentioned results arealso comparable with conventional treatment optionswhile 5�ALA and MAL topical PDT having theadvantages of better cosmetic outcome and lesser sideeffects [11–17]. Most importantly, in our study wesuccessfully treated five elderly patients (2 males and3 females) having multiple lesions, comorbids, areasof field cancerization and “difficult to treat areas”involvement with topical 5�ALA PDT which is verymuch suitable in such conditions [14, 18]. The BCClesions in our study which showed partial response (3)and recurrence (1) were all nodular and thereforeneeds long term follow up data which is available forMAL instead of 5�ALA PDT. Phase III study of MALPDT for nBCC shows 14% recurrence rate during5 years follow up [17]. Although 5�ALA�PDT hasshown efficacy in the treatment of superficial SCCsbut the relatively high recurrence rates and metastaticpotential of this serious condition have restricted therole of photodynamic therapy. There is currentlyinsufficient evidence to support the routine use of top�ical PDT for the treatment of SCCs [10, 19, 20]. Inter�national consensus guidelines were published in 2007for the use of PDT for non�melanoma skin cancers by

Braathen and colleagues [10] who recommended top�ical PDT as first line therapy in Actinic Keratosis andBowen’s disease (SCC in situ) and considered it atleast as effective as conventional therapies with advan�tages of better cosmesis and lesser side effects [21, 22].The most recent evidence along with the internationalconsensus guidelines suggest that PDT with eitherALA or MAL is efficacious for Actinic Keratosis,Bowen’s disease (SCC in situ), sBCC and may be usedwith close clinical follow�up in the case of nBCC witha preference for MAL�PDT over ALA�PDT [10, 17,19, 20]. In order to achieve maximum efficacy andminimize adverse effects of PDT, light dosimetry, druglight interval, and surface preparation of the lesionrequire optimization and standard protocols withinternational consensus.

Surface preparation varies from clinician to clini�cian and in the majority of studies, investigators pre�ferred scraping or light curettage for the surface oflesions [23, 24]. Literature review also shows the con�clusion of different investigators that fractionated lightmay be better than single illumination strategies [25].Our patients reported pain and burning sensationsduring treatment sessions. This pain was managed in

Before treatment Application of cream

After 72 hours 4 weeks post PDT

Fig. 1. Squamous cell carcinoma, skin (nose).

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different simple ways like chatting with the patient todivert the attention, a cooling fan and in approxi�mately 11% cases with severe pain, local xylocainespray used [26, 27].We have not observed any seriousside effects like phototoxic reactions except self limit�ing mild pain, stinging, erethema, edema and hyperpigmentation. We suggest further detail studies formanagement of pain during treatment and post PDTside effects. Although not in our study but literaturereview shows that Organ Transplant Recipients(OTRs) suffer from wide spread NMSCs and fieldcancerization which constitutes a major problem [28].PDT may be considered as a mean of preventing newAK lesions, SCC and BCC immunosuppressed trans�plant patient [29, 30]. While concluding, we suggestfurther detailed studies regarding optimization oftreatment protocols, development of ideal photosensi�tizers and light sources, management of pain and sideeffects for better efficacy, safety and tolerability ofphotodynamic therapy.

These results are encouraging but there is always aroom for improvement to achieve excellent clinicalresults. Specifically good understanding of the con�cept of PDT dosimetry and further application to ourstandard protocols are the critical points. In our study

it is also observed that the collaborative venturesbetween different researchers working in differentfields is also useful to produce good results. Also we areoptimistic that the introduction of new PDT photo�sensitizers will bring a great revolution in PDT arenaand in future PDT treatment in hospitals will becomea mainstream treatment choice. In short, we haveimplemented this PDT treatment and basic researchin PDT [31–44] in Pakistan with great success. Simi�larly, the other researchers [45–57] have also studiedand observed excellent results of the photodynamictherapy in different cancer cell lines.

Tuchina and Tuchin [46] studied the role ofUncovered TiO2 nanoparticles to provide bactericidalactivity against the three pathogens: Staphylococcusaureus, Escherichia coli, and Candida albicans at irra�diation by blue (405 nm) light. They found that thecombination of a photocatalyst (TiO2�nanoparticles)and a photosensitizer (methylene blue) at two�wave�length irradiation with blue (405 nm) and red (625nm) light provides a pronounced antimicrobial effect.

Tan et al. [52] discussed a novel LED source foractivating pyropheophorbids�a methyl ester (MPPa)in cisplatin�resistant ovarian cell line COC1/DDPcells. Their experimental results showed that the cyto�

Before treatment After treatment

After 72 hours 4 weeks post PDT

Fig. 2. Multiple basal cell carcinoma on face and actinic keratosis on the right side of forehead.



toxicity of LED�activated MPPa in the COC1/DDPcells increased along with the light dose of LED sourceand LED�activated MPPa resulted in light�dependentcytotoxicity. It has also been found in many treatedcells the structure of apoptotic bodies whenCOC1/DDP cells were exposed to 2 µM MPPa for

20 h and then 1 J/cm2 irradiation of LED source.Hence novel LED source could efficiently activateMPPa and LED�activated MPPa could significantlykill cisplatin�resistant ovarian cell line COC1/DDPcells through two major pathways including necrosisand apoptosis, suggesting that LED is a novel and effi�cient light source and LED�activated MPPa might bepotential therapeutic modality for treating cisplatin�resistant ovarian carcinoma.

Solovieva et al. [56] discussed the use of photody�namic therapy (PDT) for the treatment of festeringwounds and trophic ulcers. An important finding oftheir investigation is the ability of PDT to affect bacte�rial cultures that are resistant to antibiotics. Howeverthe use of PDT alone does not usually guarantee a sta�ble antiseptic effect and cannot prevent an externalinfection of wounds and burns. In their work, atten�tion is focused on the healing of the extensive soft tis�sues wounds with combined laser therapy (LT) andPDT treatment. In the first stage, festering tissues (forexample spacious purulent wounds with area morethan 100 cm2) were illuminated with high�energy laserbeam (with power 20 W). The second stage involves“softer” PDT affect, which along with the completionstages of destruction pathological cells, stimulatingthe process of wound granulation and epithelization.The major finding of their studies is that photosensi�tizer (photoditazin) is introduced inside the woundwith different amphophilic polymers for increasingthe PDT efficacy.

It is therefore concluded from the above discussionthat photodynamic therapy is an effective modality tocreate necrosis in different cancer cell lines as well asin the case of actinic keratosis, basal cell carcinoma(nodular and superficial) and Squamous Cell Carci�noma.

Fig. 3. Squamous cell carcinoma, skin (nose).

100

80

60

40

20

0AK BD BCCs SCCs

Clearance

Recurrence

Partial response

Fig. 4. Clinical experience in Pakistan (median FU 24 months).

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CONCLUSIONS

An important finding of our study is that local painrate after 5 ALA�PDT treatment is 11% as comparedto European reported pain rate of 20%. The suggestedreason for this is that large amount of melanin contentin South East Asian countries like Pakistan which leadto low skin photosensitivity as compared to Europeanwhere it is high but detailed studies are required forpain management. Hence it is concluded from ourstudies that 5�ALA PDT in an effective and safeemerging treatment modality for management ofsuperficial non�melanoma skin cancers and their pre�cursors with promising results, better cosmetic out�comes and minor side effects.

ACKNOWLEDGMENTS

We extend our special gratitude towards Prof. Dr.Ikram Ullah Khan MBBS, FRCP (UK), and Asstt.Prof. Dr. Afaq Ahmad MBBS, FCPS (Pak), Consult�ant Dermatologists, Pakistan Institute of Medical Sci�ences (PIMS), Islamabad for their valuable support interms of referring patients for photodynamic therapy.We are also very much thankful to Rector PIEAS,Director NORI, Director and Head of Medicinedepartment PAEC General Hospital who helped us alot in terms of patronage and moral support. We alsoacknowledge the valuable support by Adnan fromHMIS Department PAEC General Hospital regardingtyping of manuscript of this study.

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photodynamic therapy of non-melanoma skin cancers

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