Photodynamic Therapy of Actinic Keratosis
`With Topical 5-Aminolevulinic Acid
`
`A Pilot Dose-Ranging Study
`
`Edward W. Jeff,s, MD, PhD; Jerry L. McCullough, PhD; Gerald D. Wti11s1tln, MD; Pour E. f,rgln, MD;
`). Smarr Ntlw11. MD, PhD; To11i F. Shull, RN; Kartn R. Simpwn, MD; l.isa M. Buhaty, MD;
`Wendy L Hoffma11, MD; Nora L Fong, MD
`
`Oltlectl••• To examine the safety and efficacy ol pho(cid:173)
`todynamic therapy using 1op1cal 5-aminolevulinic acid
`(Al.A) and red light to treat actinic kcratoses (AKs).
`
`DNI . . , Actinic kera1oses were treated with topical ALA
`(concen1rarlon, ol 0%, I O'lf,, 20%, or 30%) under occlu(cid:173)
`sion for 3 hours. Before photodynamic therapy, sites were
`examined for nuorescence. Sites were irradia1cd wi1h an
`argon pumped d ye laser (630 nm) a, fluences of 10 to
`150 Jfcm'.
`
`lettf111t11 Academic medical center.
`l'etl•-• forty patients with 6 clinically typical, pre(cid:173)
`viously untreated AKs per patient.
`
`Mala Oul ■ •• M1 •• 0 1 Complete resolution and de•
`crease in lesion area of the AK relative 10 baseline evalu(cid:173)
`ared at weeks I. 4, 8, and 16.
`
`showed moderate red fluorescence. Cutaneous photo-
`1oxic effects, localized erythema and edema, peaked a,
`72 hours. Pat ients experienced mild burning and sting(cid:173)
`ing durmg light exposure. Eight weeks a lter a single
`tre:ument using 30% Al.A, there was total clearing of
`9l'K, of lesions o n the face and scalp and 45% ol lesions
`on the trunk and extremities. No significant differences
`we.re observed ln clinical re.sponses with trealment
`using 10%, 20%. or 30% ALA . All concentrations of
`ALo\ were more effective than treating AKs with vehicle
`and light.
`c-ca.•t-•: Topical photod)'namic therapy with ALA
`is an effective treatment of typical A Ks. Complete clear(cid:173)
`mg of nonhypenrophic AKs can be achieved w11h 10%.
`20%, or 30% ALA that Is easily tolerated by the patient.
`Lesions on the lace and scalp are more effectively treated
`than lesions on the trunk and exm~mities. Hypemophic
`A Ks did not respond effectively.
`
`Re..tta, Thre.e hours after ALA administrnnon, lesions
`
`Ard , fxnnatol. 1997;l.ll:727-7J2
`
`T HE APPI.IC".ATION of 5-ami(cid:173)
`
`nolevullnic acid (ALA )
`topically on skin leads to
`the accumula1ion of the en(cid:173)
`dogenous phmoscnsitlzer
`protoporphynn IX (Pp IX) in epidermal
`cdls. Conversion of ALA to Pp IX Isac(cid:173)
`complished in normal and neoplastic skin
`cells by enzymes in the heme pa1hway.
`Protoporphyrin IX is characterized by a
`bright orange-red fluo rescence and can be
`vtsualizcd in the skin when illuminated
`with a UV lnmp. The tissue-specific pho-
`1otoxjc dfrcts resulting from the topical
`administration ol exogenous ALA pro(cid:173)
`vide a basis for using ALA-induced Pp lX
`for photoclynamic therapy {PDT).1
`Photodynamic therapy using topi(cid:173)
`cal ALA has been shown efficacious in
`the treatment of various superficial epi(cid:173)
`thelial cutaneou.~ malignant neoplasms,
`includi ng basa l cell carci noma and
`
`squamous cell carcinoma in shu (Bowen
`' Topical PDT ,..,th ALA also
`disease) .'
`ha.s been reported useru l for the 1rea1-
`men1 0£ actinic keratoses (AKs) (solar
`keratoses).' 1 bu1 these studies have
`been done in only a s mall number of
`patients and have used a fixed concen •
`tratfon of ALA (20%) with filtered or
`unfiltered ,1sible light from a slide pro•
`jcctor. The purpose of this dose-ranging
`study was to determine the salety and
`clinical efficacy of topica l ALA (10%,
`20%, or JO% ALA concentration) vs
`vehicle control with visible red light
`delivered by laser for the PDT of AKs.
`
`RI ,t I 1,
`
`T hirty-nine of 1he 40 patients completed
`the 16-wcek s iudy. One patient voluntar(cid:173)
`ily withdrew after 4 weeks because of a
`schedule cnnOict.
`
`AROi 0ERMATOlM)I 13}, JUNF 1097
`727
`
`from th< V.partmtnl of
`O.rmatology (Dn Jeff.,,
`McCull.,.gh, Wdnlttin,
`ftrg1n., Nelson, Simpwn,
`Bwkmy, Hoffman, and Fon,g
`and Ms Shull) and 1hr
`Brdman taKr Jn.stirute
`(Dr Ndwn), Unn-trnty of
`Ca hforn ia, ( nirne, and the
`Vttcran.s Affairs Mtdical
`Ccnicr, I.a•~ Bcoch, Calif
`(Dr JtfT,s),
`
`

`

`Photodynamic Therapy of Actinic Keratosis
`With Topical 5-Aminolevulinic Acid
`
`A Pilot Dose-Ranging Study
`
`Edward W. Jeff,s, MD, PhD; Jerry L. McCullough, PhD; Gerald D. Wti11s1tln, MD; Pour E. f,rgln, MD;
`). Smarr Ntlw11. MD, PhD; To11i F. Shull, RN; Kartn R. Simpwn, MD; l.isa M. Buhaty, MD;
`Wendy L Hoffma11, MD; Nora L Fong, MD
`
`Oltlectl••• To examine the safety and efficacy ol pho(cid:173)
`todynamic therapy using 1op1cal 5-aminolevulinic acid
`(Al.A) and red light to treat actinic kcratoses (AKs).
`
`DNI . . , Actinic kera1oses were treated with topical ALA
`(concen1rarlon, ol 0%, I O'lf,, 20%, or 30%) under occlu(cid:173)
`sion for 3 hours. Before photodynamic therapy, sites were
`examined for nuorescence. Sites were irradia1cd wi1h an
`argon pumped d ye laser (630 nm) a, fluences of 10 to
`150 Jfcm'.
`
`lettf111t11 Academic medical center.
`l'etl•-• forty patients with 6 clinically typical, pre(cid:173)
`viously untreated AKs per patient.
`
`Mala Oul ■ •• M1 •• 0 1 Complete resolution and de•
`crease in lesion area of the AK relative 10 baseline evalu(cid:173)
`ared at weeks I. 4, 8, and 16.
`
`showed moderate red fluorescence. Cutaneous photo-
`1oxic effects, localized erythema and edema, peaked a,
`72 hours. Pat ients experienced mild burning and sting(cid:173)
`ing durmg light exposure. Eight weeks a lter a single
`tre:ument using 30% Al.A, there was total clearing of
`9l'K, of lesions o n the face and scalp and 45% ol lesions
`on the trunk and extremities. No significant differences
`we.re observed ln clinical re.sponses with trealment
`using 10%, 20%. or 30% ALA . All concentrations of
`ALo\ were more effective than treating AKs with vehicle
`and light.
`c-ca.•t-•: Topical photod)'namic therapy with ALA
`is an effective treatment of typical A Ks. Complete clear(cid:173)
`mg of nonhypenrophic AKs can be achieved w11h 10%.
`20%, or 30% ALA that Is easily tolerated by the patient.
`Lesions on the lace and scalp are more effectively treated
`than lesions on the trunk and exm~mities. Hypemophic
`A Ks did not respond effectively.
`
`Re..tta, Thre.e hours after ALA administrnnon, lesions
`
`Ard , fxnnatol. 1997;l.ll:727-7J2
`
`T HE APPI.IC".ATION of 5-ami(cid:173)
`
`nolevullnic acid (ALA )
`topically on skin leads to
`the accumula1ion of the en(cid:173)
`dogenous phmoscnsitlzer
`protoporphynn IX (Pp IX) in epidermal
`cdls. Conversion of ALA to Pp IX Isac(cid:173)
`complished in normal and neoplastic skin
`cells by enzymes in the heme pa1hway.
`Protoporphyrin IX is characterized by a
`bright orange-red fluo rescence and can be
`vtsualizcd in the skin when illuminated
`with a UV lnmp. The tissue-specific pho-
`1otoxjc dfrcts resulting from the topical
`administration ol exogenous ALA pro(cid:173)
`vide a basis for using ALA-induced Pp lX
`for photoclynamic therapy {PDT).1
`Photodynamic therapy using topi(cid:173)
`cal ALA has been shown efficacious in
`the treatment of various superficial epi(cid:173)
`thelial cutaneou.~ malignant neoplasms,
`includi ng basa l cell carci noma and
`
`squamous cell carcinoma in shu (Bowen
`' Topical PDT ,..,th ALA also
`disease) .'
`ha.s been reported useru l for the 1rea1-
`men1 0£ actinic keratoses (AKs) (solar
`keratoses).' 1 bu1 these studies have
`been done in only a s mall number of
`patients and have used a fixed concen •
`tratfon of ALA (20%) with filtered or
`unfiltered ,1sible light from a slide pro•
`jcctor. The purpose of this dose-ranging
`study was to determine the salety and
`clinical efficacy of topica l ALA (10%,
`20%, or JO% ALA concentration) vs
`vehicle control with visible red light
`delivered by laser for the PDT of AKs.
`
`RI ,t I 1,
`
`T hirty-nine of 1he 40 patients completed
`the 16-wcek s iudy. One patient voluntar(cid:173)
`ily withdrew after 4 weeks because of a
`schedule cnnOict.
`
`AROi 0ERMATOlM)I 13}, JUNF 1097
`727
`
`from th< V.partmtnl of
`O.rmatology (Dn Jeff.,,
`McCull.,.gh, Wdnlttin,
`ftrg1n., Nelson, Simpwn,
`Bwkmy, Hoffman, and Fon,g
`and Ms Shull) and 1hr
`Brdman taKr Jn.stirute
`(Dr Ndwn), Unn-trnty of
`Ca hforn ia, ( nirne, and the
`Vttcran.s Affairs Mtdical
`Ccnicr, I.a•~ Bcoch, Calif
`(Dr JtfT,s),
`
`

`

`PATIENTS AND METHODS
`
`PATIENT POPULATION
`
`For1y pa1ients (3 wometl and 37 men:, median age, 70.5years
`lrimgc, 47-83 yO'lrsl) with 6 AKs per patient were in
`eluded in the study. A total o f 21 B l,slons (grades 1-3) were
`evaluable at 8wrrks (grade I , 78lesion•; grad• 2, l 18;and
`grade 3, U). Of the 196 evaluable grndc 1 and 2 lcsions,
`128 were on 1he lrunk and extremilies and 68 were on the
`face and scalp. Of the 22 grade 3 lesions, 21 were on the
`rrunk and ex1remides and t was on 1hc face or scalp The
`larges:1 diameter or the lesions ranged from l mm to 2. 1
`e:rn (median, 9 mm). PalientswereexcJuded ,r they h::ad re.(cid:173)
`ceivtd rrea1ment of targe1 A Ks, or af they had used topic.al
`con icosleroids (previous 2 weeks); 1opi~l « •hydroxy ac(cid:173)
`ids or S)'S1em1c corucos1er01ds (prcVIOUS 4 week$); or sys(cid:173)
`temic re:1ino1ds, chemotherapeutic ;igents. or 1mmuno(cid:173)
`therapy (previous 6 months). Pregnant or nursing women
`or patiems wi1h a history or cutaneous photo.stnsiuvity a.lso
`were excluded. The study was approved by the Uaivcr,;ity
`or Calirornia, hv,ne, Human Subject Research Commit(cid:173)
`tee. Each pati.cn1 re«:ivttl comptthmsivt infonnatK>n aboul
`the nature or the study and written informed const:nt was
`obtained before rccrui1ment.
`DRUG APPLICA no
`
`Before applkation. Al.A was adm1xttl wi1l1 u proprietary
`emollient vehide (M 55A. OUSA Phann.aceuticals lnc.
`Tarrytown, NY) to produce concentrations of 10%, 20%,
`and 30%. 5,.AmlnolcV\1li11ic: add teSl preparations at con•
`cemrations or 0%, 10%. 20%, or 30% we.re assigned 10
`patitntS on a nonblinded basis. All 6 ShC$ on a patien1
`were trea1ed with Lhe- same conc,nmllion of A.l.J\~ Ahe.r
`applying ALA 10 target lesions and JO to 20 mm ol sur(cid:173)
`rounding nornta1 skin, 1~ 1 Siles were covered \Vltb an
`ildhesive. skin-colo red, aluminlzed ocdus1ve tape- (3M
`Pharma<.-cuticals, St Paul, Minn) 10 prevent exposure to
`ambient light. Three- hours ahtr ALA Jpplic:,Uion. immc:::4
`diiuely ht-fort assessment or nuorC$Cen cc, the l3~ W3$
`removed and the- a rea "'"iped to re.mQYC cxcc.\S <lrug Crom
`the skin.
`
`ASSESSMENT OF FLUORESCENCE
`
`Immediately before ligbt treatment. Ouorescence of the
`trca1ed lesions and surrounding normal skin was exam•
`incd visually using a UV lamp (mod<i 8-100 AP, UVP, San
`Gahriel, CaliO containing• mercury Oood la.mp (model H-+I
`JM-100, Sylvania). Fluor<.SCence inttnsity was scored as 0,
`none~ I. weak: 2.. moderate:~ or 3. intense.
`
`LIGHT TREATMENT
`
`An argon pumped dye lmr (modtl 920, Cohertnt Medi(cid:173)
`cal. Palo Alto, CaliO tuned to emit radiation a, 630:!:l nm
`was used for the: ligh1 treatments. A remote fiber spHne:r
`(model 1025. 1..as<rlhcrapwtli:s, Buelton, CaliO permit(cid:173)
`Led simultaneous laser ;rF1-<liation of 1rea1me:.m sites. Each
`('iberoplic terminated in a microlcns that focused 1he laser
`radiation onto a 2<m-dtameter circul:,u ftdd or unifonn light
`intensit)'. Laser irradiation emanating rrom 1he fiber was
`
`monitored with a power mett.r (model 2 lO, Coherent Mtdi·
`cal) before, during, and afm treatment. The power den(cid:173)
`sity of the loser inadlatton was gradu.tlly escalated (50, 100,
`150 mW/cm') ln the Orst 10 patients 10 = s tolerance
`and ..Cety. Because these patientS easily tolerated all the
`powe:r de-nsllits afld there was no d iffcre.nc:e. in p.alie:.n1 tol•
`erance at low and high power densities. the last JO pa(cid:173)
`tients were treated using 150 mW/cm' . Each ol the 6 AKs
`on each pa1ien1 were treated with I of the following Ou(cid:173)
`ences: JO, 25, 50, 75, 100, or 150 J/cm•.
`
`CLINICAL ASSESSMENT
`
`Sarety and clinical ru.ses..~rnents were p,e.rformed at base•
`line, immediately after PDT, and at 2◄ and 72 hours and at
`I, 4, 8, and 16 wed,s after PDT. Clinically typical AKs were
`~ le.cted by trained investigators as scaly crythcmatous pap(cid:173)
`ules a11d plaques de\'Oid of cystic pores or• papiUomatous
`surface (to excluded seborrh<ic keratosis and verrucae). &(cid:173)
`cause having 6 lesions was required to enter the st udy, the
`patients had se-•erc solar damage and had many AKs. of
`whkh only typical, easily evaluable lesioas were sekct<d.
`Wions were clmicat1y graded using crir.cria similar to those
`reported by 01.w ct al,' which were u54:d to cva.luate AKs
`treated with masoprocol cream. The criteria lor each grade
`of AK are I , easily sw,. with slightly palpable byperku:a-
`1osis (a tl11n AK); 2, easily seen and wtll-<leveloped. easily
`palpated hyperkeratosis ( typical wcll-dcvtlop«l AK); or 3,
`thick hyperkeratosis. evidence for thickened cpldcm,ls a,
`margin of the AK. or both (hypcrtroph ic or hyperker.a(cid:173)
`totic AK). The dimensions ol the AK w,rc musured and
`arc-11 (1TX 1/, lengthX'/, width) was calculated. Clinical re(cid:173)
`spon.St! W'JS defined a.\ the percentage rcduc:tk>n of prcrrieat(cid:173)
`ment lesion area and ra1edascomplete r,.ponse (CR),dcar
`of palpable or visible lesion; partial response (PR), bc-
`1wttn SO% and 100% reduction in lesion are-a; or no rt(cid:173)
`::.ponse (NR). I~ 1ha1t 5°" reduction in les·ion area. Le·
`.sions 1hat did not have:: a CR al wee.k 16 were treated With
`hquid nilrogc-n~ Befort and i0Unediately afte.r POT and a t
`each su~qucnl v1$il, n e.aunent sites we:tt e:valuated for
`objecttv~ ch:mgts, induding whea)..Clue re,icttOns (0, none,
`I, minimal or barely perc~ptiblc; 2, mode rate; and 3. se(cid:173)
`vere), skin phototoxlc effects (0, none; 1, minima~ asymp(cid:173)
`tomadc cryth~ma~ 2, moder-ate e.rylhe:ma with prurilus or
`edema; l , severe c:rythcma with mod~ratt to severe edema~
`and 4, skin ulceration). Subject assessment of paH~n l dis(cid:173)
`comfon [rom pain, burning and slinging, and itching was
`gr~dcd a-. 0, none; I , slighti 2, m.oder:ue:; 3, severe-~ or 4.
`very severe), Stand:rrd hematologic and biochemical labo(cid:173)
`ratory values were cvalua1ed at bascfinr :ind again at I week
`after PDT Unne ALA was measured al ba$Cltnc and at 24
`hours after ALA applkation, Safety or the treatmen1.s wa.s
`asStSsed by adverse events, the POT response.. and labora-
`10ry results.
`The Studenr r test W2S used l o compare qwntit;3;t1,•c
`vari.ables. Summary scatistics are e:xpressed as me;an±SD.
`Oiffcrtnct"S in clinical tesponse berween rrea1mem vari•
`obles were tested usi ng the x' test. or the Fisher test
`lor small sample numbers. The Speann•n rank order
`correlaliun was used l O evalua1e the relauon betwe-e:n
`fluorescence. photo10xic cffec-is, d i..scomfon, and climcal
`rc.sponse. Linea r regression was use:d to evaluate
`1he relation between response and ligh t nuence
`administered.
`
`ARCH OERMAT()UVOL 133, JUNE 1997
`718
`
`

`

`■ IDUUI ■ ..... AUi ■ '°' .l!A
`, .. ,"°l
`,..,~
`n.361
`
`to
`
`, ..
`.. to I:
`i: ,o a.....__.,_
`
`FIIJ•re 2. ~ ,at• ol aN r;mJe t aM 2 /lypir;a/) acw,;c ;e,,tos,s
`trutlld wilh 5,am/noltWJlinic ll!ld /Al.A/ pllO/odyrllmic t"'1apy.
`
`to
`1'. ) O
`
`, .. ..
`i t,O J so
`i '° ! 3e
`29 ,.
`o.L~=- - - - -= •
`T1mt ,\hllf PhohxlyNl'Tllc ThmlJ'f. vi'\
`
`16
`
`Fi9ure 1. Actinic k""'10S6S /Ml 1/voresCMt:61Met lop/cill 5-aminolMJfinlc
`lcid IIUI-. Toi, Ind Ctllltr. Weak huOr,$C,nct of I</( . . txllemily.
`wJth minimal fJuores«J)Ct ol ldjl!Cffll normal Skitl. Bottom. More ;m,nse
`flllOftSC8'1Cf of AK .. SCl,'P, m/h significant IIIJortsunc, ol lldjactnt
`no,m,/,appUttng $IJll•<lam1ge<1 skin.
`
`Pp IX FLUORESCENCE
`
`Three hours of occluded applka1ion of ALA cream pro•
`duced weak to moderate red Ouorescence of grade I to
`2 AKs a1 all concentrations of ALA. There was no sig(cid:173)
`nificant difference between AKs 1rea1cd with 10%. 20%.
`or 30% ALA. Thick, hyperkera101ic grade 3 A Ks showed
`s,gniflcamly less Ouorescence. The surrounding nomial(cid:173)
`appearing sun-damaged skin 1rea1ed with ALA showed
`a lesser degree of Ouorescencc. This selec1ivity was less
`pronounced on areas of the face and scalp. where both
`lrsion and adjacent skin showed moderate nuores(cid:173)
`cencr, with the AKs Ouorescing brighter 1han the sur(cid:173)
`
`rounding sun-damaged skin <••- 1 ).
`
`CLINICAL RESPONSE
`
`The clinical response rate of grade I and 2 A Ks and grade
`3 AKs at ◄. 8 , and 16 weeks after PDT is shown i n
`Fl9u,. 2 and Flt.,.. 3 , respectively. Maximum clini(cid:173)
`cal improvement was obtained with treatment of grade
`I and 2 lcsions with 30% ALA (61%, CR; 26%, PR). The
`clintcal response of grade 1 and 2 A Ks treated w11h 10%.
`
`Figu,e 3. Re$/NJI& ram of al gmJe 3 (lhi<ll 1ryp,Jk•1•totic) actrnic
`ke,atoses rrwell wiltl 5•aminalevulfnic aod /ALA/ photodynam/c l/lerapy.
`
`20%, o r 30% ALA and light was signilicant ly better than
`A Ks treated wi1h vehicle and ligh1 (P< .001 ) . Thick. hy(cid:173)
`perktratotic grade 3 A Ks did not respond c1Tcc1ivcly 10
`trcaLmcnl with 20% or 30% ALA.
`Actinic keraioses on , he face and scalp responded
`significantly better 10 treatment with ALA and light com(cid:173)
`P"rtd with A Ks treated on the tnmk and extremities when
`20% or 30% ALA was used 10 pho10sensi1i2e the lesions
`(P<.05) (T■We I ). The percentage of AKs on the face
`and scalp ( n= 11) treated with 30% Al.A and light hav(cid:173)
`ing a CR was 91%, while 45% o[ the AKs on the trunk
`and extremities ( n= 20) had a CR when treated id<nli(cid:173)
`cally (P<.05). The response distribution was not slgnlfi(cid:173)
`can1 ly different for A Ks treated with 10% ALA and light
`when the face and scalp (n= I 3) was compared with trunk
`and extrcmiues (11=23). The mean percentage improve(cid:173)
`ment as measured by reduc1 ion in lesion area of face and
`scalp A Ks was 90% 10 99% vs 58% 10 62% for trunk and
`extremity lesions treated with 10% to 30% AL'\.
`The CR rate or all grade I and 2 AKs trea1ed with
`20% ALA at Ouences or 10 10 150 )/cm' is shown in
`, . ._ 4 . Analysis ol 1hese data shows that a maximal
`CR rate was achieved at 10 Jlcm' . and this was not s ta(cid:173)
`tistically dilTerenl from the CR rate observed at 150 J/cm1.
`Similarly, PDT with 20% ALA produced a maximum de(cid:173)
`crease In leslonal area at JO j/cm' and there was no In-
`
`AR(.tt otRMATOINOt I}}, JUNf 1'>97
`119
`
`

`

`T•-1• 1. Cllaiul Rnp- II flCI ltld Scalp
`vs Trull 11111 btrtlllltin Ac1111c KnloAs l&ralln 1
`IM 2) II I WNb Aller Pl 111 lfnallllc Tllan,y•
`
`Tnall1odfJlnmllln
`
`%Al.A
`ot
`IOI
`20t
`30f
`
`CR
`0
`8(61)
`24 (78)
`10 (91)
`
`I'll
`6(46)
`4 (31)
`6(19)
`1 (9)
`
`11A
`7(54)
`1 (8)
`1 (3)
`0
`
`CA
`1 (6)
`7 (30)
`26 (38)
`9 (45)
`
`1111
`12 (75)
`8 (35)
`19 (27)
`4 (20)
`
`3 (19)
`6 (35)
`24 (35)
`7 (35)
`
`• ALA indiu/,s 5-dminolellu/inlc acid; CR, comp/ft/I mponse; PR, pa11,a1
`rsspans1; and NR, no ~ e . O.tra a,, (KIUtlJ«l as total rwml)tf of
`atlil!ic k"1tos,s sires trest/Jd with desjgnatl!d response. wlttl w
`perrM111g, ol ilCl>nic kmtOSIS sites trea11d with designated tOSJJ()llse In
`par,ntheses.
`t Respo,ise dis/ribut!on on face and scalp is oot d/MBTBfll from t/11/lt and
`txlftmilin (Fishot exact test. P> .05).
`tResponse dis/rilwtion on /au and scalp shows a siQ,1/ficant/y
`lm/Jfover/ response when comp,1"1 witfl lroak and ,xtr,miries (Jf, F1$h#f
`IXilCf tis/; P<.05),
`
`100
`90
`ao
`' : 71) 16')
`i !()
`i '°
`i "'
`u
`20
`
`10
`0
`
`....
`
`Fllun 4. Comf)klt response ,.,, ,r 8 .,..,,. of aN (PII• t and 2 ltsloM
`5•amlnoie.utlnlc acia (ALA) II MJfncts of 10 IO
`"'""' w/Jh -
`150.J/rm.
`
`crease in effeco wioh trea1ment at the higher fluences ( 10-
`150 J/cm') (Student r test. P > .05). A further linear
`regression analy~is showed a maximum effect on le•
`siona.l area at 10 j/cm' that did not increase with Ou(cid:173)
`cnces up to 150Jlcm' (R'~0.005; P•.➔8). Thcsc data sug(cid:173)
`gest that a maximal response had been reached al !OJ/cm'
`and 1ha1 the response did 1101 increase with higher light
`Ouences up 10 150 J/cm 1.
`T he.re was a significant correlation of AK Fluores(cid:173)
`cence with improved climcal response (r_.le 2 ). There
`also was a significant correla1 ion ofnuorescence with In(cid:173)
`creasing pho1otoxlc effects on the AK and surrounding
`skin. but no correlation with subjective discomfort re•
`ported by the patitnt during Light trcauncm.
`The thicker grade 3 lesions did not respond well to
`PDT at any concentration of Al.A compared with thin(cid:173)
`ner 1ypical grade I 10 2 A Ks. Because mos! of 1he grade
`3 hypertrophic AKs treated in this study were on the ex(cid:173)
`tremities. we compared the response of grade I and 2 thin
`AKs with grade 3 thick AKs, limiting the A Ks 10 the trunk
`and extremities treated with 20% AlA Grade I and 2 AJ<s
`on the trunk a nd extrem ities decreased in area by
`58%:!:62% ( n=68). and grade 3 A Ks in the same regions
`
`Tallle 2. Comllllllll II F I i i - anti PINllllallc
`Elledl Wllll Cllnlcal 'larta•lfl ill Grallfl 1 1M Z
`Acllalc KlfltaN Tl9111i Wltll 20% 5-AmlNltwlllllc
`
`Adf ,.._.,..mlc Tlleran
`
`Auomcenct vs clilical response
`flllorescence YS pllototoxlcily
`AIIO<OS<ence YS dlscomfor1
`Pllototoxicily vs clinical response
`
`0.35
`028
`-0.02
`024
`
`,
`
`<.001
`.005
`.76
`.ll2
`
`• See m, "Patients and Mt/lood$" -
`scalfsl/Std.
`
`tor• tlo$<rip/ion ol the cltnicd/
`
`decreased in area by 2➔%:!:24% (n=ll). a significant dif(cid:173)
`ference (P <.05). A similar nonparametric analysis of the
`same data showed that grade I and 2 AKs had 26 CR and
`➔O PR und NR, and grade 3 AKs had OCR and 11 PR and
`NR, again a significant difference (P<.02, Fisher exact
`test) . Thus. thick AKs on the trunk and extremities do
`not respond as well as typical thinner AKs in the same
`region of the body. There were not enough thick hyper(cid:173)
`trophi.c AKs treated on the face and scalp to do a similar
`analysis on this site.
`
`C LINICAL EFFECTS OF PDT
`
`The.re were mild phototoxic effects on lhe ALA-treated
`sites, which were manifest by localized erythcma and
`edema that peaked 72 hours 10 I week aher PDT and re(cid:173)
`solved by week 4 (Fl9• .. S ) . In general, the photo(cid:173)
`toxic effects on the treated adjacent sun-damaged skin
`were much less than on the AKs. Pho1odynamic 1 herapy
`resulted in s uperficial erosion or many or 1he AKs with(cid:173)
`out eroding surrounding nonnal skin.
`All patients experienced mild 10 moderate discom(cid:173)
`fort during light trealment (Fl .... 6 ), which was mani(cid:173)
`res, b)' burn ing and >1inging at the treatment site that
`started and was most severe with the beginning of irra(cid:173)
`diation, decreased during the irradiation, and stopped im(cid:173)
`mediately when the irradiation was terminated. The treat(cid:173)
`ment was well tolerated by most patients. There was no
`observable difference in patient discomfort during or af(cid:173)
`ter ligh1 rrea1men1 at power densities ranging from 25
`10 150 mW/cm'. All patients but I were able to com(cid:173)
`ple1e 1he light 1rea1men1s at all Ouences. A wheal-and(cid:173)
`nare rt'.action developed immediately after treatment in
`14%of the treated lesions (mean intensity, 1.4; scale, 0-3).
`The cosmetic rcsuhs of the PDT were excellent. wit h le(cid:173)
`sions clearing without persistent pigmentary alterations
`or scarring ( F19u .. 7 ). There were no clinically signifi(cid:173)
`cant abnormalities in laboratory tests and no significant
`changes from baseline of urine AlA measured at 24 hours.
`
`< \ l\l\111\ I
`
`T he result< of thi< study show that PDT with a single treat•
`ment using topical ALA and visible red light is highly cf.
`fcctlvc for the treatment of typical AKs (grade I and 2 in
`this study). A single topic.al application of 30% Al.A for
`3 hours followed by treatment with red light resulted in
`
`ARCII OERMAT0L/V0L I J), JUN[ 1997
`no
`
`

`

`3
`
`• •
`
`•
`
`hnr A.:1!'1 Pl'lotof)lrafl'At n1erac,y
`
`Figure 5. Cuuneous p/POlOtOX}C ertecfS ol pholodyfJllniC lherdPY wi'm
`10%. 20!' and~ 5·"1lina!e'IVMH: acid (AJ A} P/l()lotOX/1; · (cid:173)
`was q,atMd as o. """" 1, ,rn/f/ 1uy1-.1: 2. m<)de,ate (e,y1nema {Ill(/
`edfnU/, 3, sev,,. /"Y'ntm• and"''""/: and<. n,c,o,;, of Skin.
`
`■ 1KAU.
`
`• ~ALA
`
`10
`
`:; 1
`
`" II
`9 •
`l•
`3.
`" •
`
`3
`?
`• ·,•=-:I~
`/
`-
`-
`· - ·
`'
`o-'--'-~· - - -~ =::_..:-,.e= ~ =-~f-'--+--'"'
`I,._
`72 h
`
`, ..
`
`Figure 6. suo,,c,;.. r!lscomfort from pootodymm,c 1/Jer,py Wflh 10%.
`20%. and 30% 5·amino/evu/f(I/C acid (AU./ nie cKscomlort sCJ/4 iS
`composed of 3 a>111POnents {/>lin, burnmq and sJ,no,np, and liCflmO/. u,;r,
`~ • scc,e of o to , I• tolill IT/,JJ/IITlum scor, ot 12) 0/#om/Ort was
`gratkJJ ,so, nc,,~ t, mild 2. m<)d,rat,, 1 sm'tlt; md ,, "''l' _ ,_
`
`Fl1ure 7. Typieat dm,ut r,sponse ol at:1N11C Jwatom JIWwn bttor!
`UUtmfnl (top/ and 8 -
`k$ ah,r phOIQt/y1Wllir: lh<rapy (boffom/.
`
`rnmpl<te clearing of 6 1% or typical grade I ;,nd 2 AK,,,
`The complete cleari ng response rates of grade I and 2
`A Ks treated with 10%, 20%. or 30%ALA (42%, 50%,and
`6 l 'fi. respectively) were signi[icantly bc11crthan the 3%
`cornplc1e cle:mng or A Ks trea1c<l with vehicle and red light.
`The paticms' acceptance or the treatment regimen was
`good, as assessed by subjecLive measurt"mcnts or discom ..
`fon and comple1ion or all treatments. All patienas re(cid:173)
`pon c<l discomfort during the ligh1 exposure but did not
`rec1uire 10<:al anes1 hesia, unlike that reporied for treat(cid:173)
`meni or deeper cuianeous tumors.'·'
`1\ s1gnif'icantly better response was seen for th~ lrc~lt·
`ment of AKs on the lace and scalp with 20% or 30% Al.A
`and light, compared wiu1 AK, on the trunk and extremi(cid:173)
`ties There was complete resolution in 9 1 % orlace and
`scalp A Ks treated with 30% ALA and ligh1, but AKs at
`01her sites (1runk and extrcmilit.'S) had only ➔5% CR.
`Thick , hyperkeratotic lesions did no1 respond er(cid:173)
`rcctivcl)' LO POT. Even considering that mo,1 or 1hc hy(cid:173)
`pertrophic AK, were on the lrunk and extremilic.<, the
`response or the thick lesions was significantly less than
`1hc typical lesions. There was :rn inverse cor-rclalion of
`
`nuorescence (ic, Pp IX produc1ion) ar1er topical appli(cid:173)
`cation or ALA wi1lt the grade of the AK. The h)'!)l'rtro(cid:173)
`phic A Ks commonly did not fluoresce. This may be due
`10 meffec1ive pcnetra1ion or ALA and the consequem lack
`or conversion 10 Pp TX. Wi1h kss Pp IX produced In 1he
`hypc nrophic AK, a poor respo nse rate would be
`expcc1ed.
`Other topical 1herapics also are lcsseffecuve in treat(cid:173)
`ing A Ks on the extremilies and thick hypenropluc AKs.'~
`Few studies have cvalua1ed the response rate or AKs a1
`sues other 1han the head and neck. ilercovitch• reported
`a cli111cnl irlal treotrng AKs or 1he upper e<tremity with
`nuorouracil and achieved a C:R rate or 78%. This re(cid:173)
`sponse rate is similar to reports or Ouorouraci l thempy
`for the he:.d and neck. In our experience (;tnd in 01hcr
`reports), 1opical nuorourac,1 lherapy or AKs on the CX·
`ltnsor arms usually rtprestni< a more difficuh therapeu-
`1ic challenge 1han 1rca1ing A Ks on the head and neck 7~
`We also find ii routinely necessary 10 use locally destruc(cid:173)
`tive iechniques (aggressive use or liquid nitrogen, or cu(cid:173)
`renage and electrodesicca11on) Lo treat effec1iv<ly hyper(cid:173)
`trophic AKs on 1he trunk and extrcmuies.
`
`r\Rflt OERMAH)L/VOL Ill. fUNE 19Q7
`7)1
`
`

`

`The rcsullS of this study are consistent with previ(cid:173)
`ous observations of a good clinical response of typical
`AKs 10 PDT with ALA. '-' Most POT studies with porphy(cid:173)
`rin for treatment of cutaneous lesions have u,ed red light
`because of deeper light penetration in human skin. In this
`study. we used a red laser light source 10 maximize the
`activation of the Pp IX at all levels of the skin and su(cid:173)
`perficial dermis in an auempt 10 induce the greatest re(cid:173)
`spol15" of the AK and 10 maximize clinical cure rate. The
`las-,r light source used ln this study supplied a pure light
`source that could be administered at high Ouences. This
`light source obviously could not be used easily in the
`clinic. Various other light sources could theoretically be
`developed that are more clinically relevanL Because Pp
`IX has a maximum absorption at 4 IO nm (Soret band).
`shorter wavelengths may be effective in treating supcr(cid:173)
`flclal A Ks and have the advantage of reducing the light
`exposure times. Full-spectrum unfiltered visible light
`(400-700 nm) has been shown dlective in the treat(cid:173)
`ment of AK1
`The respons,: rate of face and scalp AKs 10 topical
`POT with ALA is similar to that reported for topical fluo(cid:173)
`rourn.cil cream. masoprocol cream, chemical peels. or liq(cid:173)
`uid nitrogen therapy. Lawrence et al 10 reported a 75% CR
`rate of facial AKs created with fluorouracil cream twice
`daily and tretinoin daily for 3 weeks. Pearlman " re(cid:173)
`ported a 98% CR rate of facial A Ks treated with Ouoro(cid:173)
`uracil cream once or twice weekly for 7 weeks. Maso(cid:173)
`procol I hcrapy of head and neck AKs twice daily for up
`to 28 days resulted in a 71 % decrease in total numbecr of
`treated A Ks.6 Therapy of facial A Ks with a J essner solu(cid:173)
`tion and 35% 1richloroace1ic acid chemical peel re(cid:173)
`sulted in a 75% CR rate evaluated I month after 1herapy.1•
`Lubrit.z and Smolewsk1 11 reported In a limited Sllldy of
`aggressive liquid nitrogen lherapy of AK, a CR rate of 99%
`with a I-year follow-up. In our study, therapy of facial
`AKs with 30% ALA and light resulted in a 91 % CR rate 2
`months after PDT.
`Photodynamic therapy for the treatment of AKs
`may offer .several advantages O\'er conventional topical
`chemotherapy. chemical peels. or liquid nitrogen .
`Daily therapy with fluorouracil and masoprocol typi •
`cally involves treatment that lasts £or several weeks 10
`achieve clinical efficacy. During Lhis treatment inter(cid:173)
`val, these therapies produce a no table amount of local
`erythema, crusting, and discomfort that may be unac•
`ceptable 10 patien1S.6·" Weekly '' pulse• dosing with
`topical fluorouracil has decreased the magnitude of
`erythema and elimlna1e_d most of Lhe crusting. but still
`requ ires therapy for about 7 weeks.11 Peels with Jess•
`ner solution and 1richloroace1tc acid may be an effec(cid:173)
`tive alternative therapy 1ha1 is administered once and
`results in about a 2-week healing phase in which the
`cosmetic appearance may be compromised.•• Photody(cid:173)
`namic therapy "1th ALA is similar 10 a peel and liquid
`nitrogen therapy in that it is accomplished with a
`single treatment and results in a 2-week healing phase.
`Photodynamic therapy with ALA may have the advan(cid:173)
`tage of being more selective than chemic.11 peels and
`liquid nitrogen in direct ing the maximal injury 10 the
`
`AKs with relative sparing of the surrounding skin.
`This selectivity probably reflects more rapid conver(cid:173)
`sion of ALA to Pp IX and a higher concentration of Pp
`IX in the AK compared with the ,urrouudlng skin.
`Photodynamic therapy with ALA has a similar cure
`rate to liquid nitrogen therapy. In conclus1on , POT
`with ALA of AKs may combine Lhc s,:lectivily of topi(cid:173)
`cal fluorouracil Lherapy with the advantage or single
`trea1mem of peels and liquid nilrogtll Lherapy, and a
`cure rate similar to all the modalities discussed.M·11· "
`
`Accepwl for publfcarlon Dtctmber 5, 1996.
`This study was supported in pan by a gr<1J1t from
`OUSA Pliannac,ulicals Inc, and by grants I R29 AR4 I 638
`and !ROI AR42437 from the N111lo11al lnstitutts of Health,
`Bethesda, Md (Dr Nelson).
`Presenttd at rJ,e 55th National Mttting of tht Sod(cid:173)
`ety of Investigative Dcnnatology, Baltimore, Md, April 28,
`199'1, and tht 15th Aitnual Metting of the American So(cid:173)
`dtty for Laser Mtdici11e, San Diego, Calif, April 2. 1995.
`We acknowledge the consultation of Ally n Golub, PhD,
`Guidtlin,s Inc, Miramar, Fla, <1J1d tht assistance of Di(cid:173)
`anne Moudy, Clinical Study Administrator.
`Reprints: Edwcird W . Jtffts. MO, PhD, Otpartn1en1
`of Dmnaiology, CHO Medical Sciencrs, University of Cali(cid:173)
`fornia, Irvine, Irvine, CA 92717.
`
`------i•ii■liiliihh•f------
`1 KMnedy JC. Poner RH. Endooenous "''"oporpllyMn IX, , cllrll<illf usolvl pho(cid:173)
`"''"""~' 1"' ~IXlynamic U•apy. J Pl10t()CtlMll'IIOIObidB. 1992.'6:27S-292.
`2. S21.m,es A-M. S.Ssy T. l.andlllalef M. PtnetrltlM pOlency of t<ljlical ll'C)ied
`&--1minole\lulinic acid for photodyr.amic Cherapy of basal 011 wcinoma. Pho(cid:173)
`,_ Pllt/lOCiOI 8. 1994,59:73-78.
`3. WOif P. A119<1 E. K"1 H. T~ photOOynamlc lh!lflpy ... ,h "'dot.I"'°"' l)Of·
`p.1yriM afler 1ppllcat1on cf 5-a~ acid, J .Am kMJ o,r,n,,_o1, 1993,
`28:17-21.
`• C>J1ndu