intralesional chemotherapy for nonmelanoma skin cancer: a practical review

14
Intralesional chemotherapy for nonmelanoma skin cancer: A practical review Joslyn S. Kirby, MD, a and Christopher J. Miller, MD b Hershey and Philadelphia, Pennsylvania Intralesional chemotherapy for nonmelanoma skin cancer has existed for more than 5 decades. However, it is used so infrequently that recent consensus guidelines for the treatment of basal cell and squamous cell carcinoma do not include intralesional chemotherapy. Barriers to the use of intralesional chemotherapy include the off-label use of these agents, absence of therapeutic guidelines, a relatively small number of patients treated, and a lack of large, well-designed trials with long-term follow-up. Surgical intervention remains the gold standard for the treatment of nonmelanoma skin cancer; however, intralesional chemo- therapy remains an option for well-selected patients who cannot or will not undergo surgery. The objectives of this article are to determine response rates and suggest reasonable treatment guidelines for the treatment of squamous cell carcinoma, keratoacanthoma, and basal cell carcinoma with the most widely available intralesional agents (methotrexate, 5-fluorouracil, bleomycin, and interferon). ( J Am Acad Dermatol 2010;63:689-702.) Key words: basal cell carcinoma; bleomycin; chemotherapy; fluorouracil; interferon; intralesional; keratoacanthoma; methotrexate; squamous cell carcinoma. I ntralesional chemotherapy is occasionally used to treat skin cancer, but recent consensus guide- lines for the treatment of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) do not include intralesional chemotherapy. 1 Methotrexate (MTX), 5-fluoruracil (5FU), bleomycin, and inter- feron solutions are labeled for intravenous or sub- cutaneous administration. The fact that intralesional use of these agents is not reflected in product labeling may discourage physicians from using them. Similarly, the lack of large well-designed trials or guidelines for the use of intralesional chemother- apy leaves the clinician with little evidence to guide practical management decisions. The existing literature varies widely in choice of intralesional agent, method of intralesional adminis- tration, concentration of the medication, dose per treatment, frequency of treatment, duration of treat- ment, and use of laboratory monitoring. Without data to support treatment recommendations and limited experience with the use of these agents, patient counseling becomes difficult, especially be- cause most tumors eligible for intralesional chemo- therapy have already presented management dilemmas. By summarizing the literature, this com- prehensive review may help clinicians use intrale- sional chemotherapy to treat SCC, KA, and BCC with greater confidence and safety. METHODS A search of the MEDLINE database (1950-present) was conducted to identify original studies evaluating intralesional chemotherapy agents as the main ther- apy of nonmelanoma skin cancer (NMSC). The terms ‘‘squamous cell carcinoma,’’ ‘‘basal cell carcinoma,’’ ‘‘keratoacanthoma,’’ ‘‘fluorouracil,’’ ‘‘methotrexate,’’ ‘‘bleomycin,’’ and ‘‘interferon’’ were used in Abbreviations used: BCC: basal cell carcinoma CR: complete response 5FU: 5-fluoruracil KA: keratoacanthoma MTX: methotrexate NMSC: nonmelanoma skin cancer SCC: squamous cell carcinoma SCCis: squamous cell carcinoma in situ From the Department of Dermatology, Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, a and Depart- ment of Dermatology, University of Pennsylvania, Philadelphia. b Funding sources: None. Conflicts of interest: None declared. Presented as a poster at the Annual Meeting of the American Society for Dermatologic Surgery, Orlando, FL, November 8, 2008. Reprint requests: Joslyn S. Kirby, MD, Department of Dermatology, Milton S. Hershey Medical Center, Penn State College of Medicine, 500 University Dr, Hershey, PA 17033. E-mail: [email protected]. Published online June 1, 2010. 0190-9622/$36.00 ª 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.09.048 689

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Page 1: Intralesional chemotherapy for nonmelanoma skin cancer: A practical review

Intralesional chemotherapy for nonmelanoma skincancer: A practical review

Joslyn S. Kirby, MD,a and Christopher J. Miller, MDb

Hershey and Philadelphia, Pennsylvania

From

C

m

Fund

Conf

Prese

fo

Repr

M

M

jk

Publ

0190

ª 20

doi:1

Intralesional chemotherapy for nonmelanoma skin cancer has existed for more than 5 decades. However, it isused so infrequently that recent consensus guidelines for the treatment of basal cell and squamous cellcarcinoma do not include intralesional chemotherapy. Barriers to the use of intralesional chemotherapyinclude the off-label use of these agents, absence of therapeutic guidelines, a relatively small number ofpatients treated, and a lack of large, well-designed trials with long-term follow-up. Surgical interventionremains the gold standard for the treatment of nonmelanoma skin cancer; however, intralesional chemo-therapy remains an option for well-selected patients who cannot or will not undergo surgery. The objectives ofthis article are to determine response rates and suggest reasonable treatment guidelines for the treatment ofsquamous cell carcinoma, keratoacanthoma, and basal cell carcinoma with the most widely availableintralesional agents (methotrexate, 5-fluorouracil, bleomycin, and interferon). ( J Am Acad Dermatol2010;63:689-702.)

Key words: basal cell carcinoma; bleomycin; chemotherapy; fluorouracil; interferon; intralesional;keratoacanthoma; methotrexate; squamous cell carcinoma.

Abbreviations used:

BCC: basal cell carcinomaCR: complete response5FU: 5-fluoruracilKA: keratoacanthomaMTX: methotrexateNMSC: nonmelanoma skin cancerSCC: squamous cell carcinomaSCCis: squamous cell carcinoma in situ

Intralesional chemotherapy is occasionally usedto treat skin cancer, but recent consensus guide-lines for the treatment of basal cell carcinoma

(BCC) and squamous cell carcinoma (SCC) do notinclude intralesional chemotherapy.1 Methotrexate(MTX), 5-fluoruracil (5FU), bleomycin, and inter-feron solutions are labeled for intravenous or sub-cutaneous administration. The fact that intralesionaluse of these agents is not reflected in productlabeling may discourage physicians from usingthem. Similarly, the lack of large well-designed trialsor guidelines for the use of intralesional chemother-apy leaves the clinician with little evidence to guidepractical management decisions.

The existing literature varies widely in choice ofintralesional agent, method of intralesional adminis-tration, concentration of the medication, dose per

the Department of Dermatology, Milton S. Hershey Medical

enter, Penn State College of Medicine, Hershey,a and Depart-

ent of Dermatology, University of Pennsylvania, Philadelphia.b

ing sources: None.

licts of interest: None declared.

nted as a poster at the Annual Meeting of the American Society

r Dermatologic Surgery, Orlando, FL, November 8, 2008.

int requests: Joslyn S. Kirby, MD, Department of Dermatology,

ilton S. Hershey Medical Center, Penn State College of

edicine, 500 University Dr, Hershey, PA 17033. E-mail:

[email protected].

ished online June 1, 2010.

-9622/$36.00

09 by the American Academy of Dermatology, Inc.

0.1016/j.jaad.2009.09.048

treatment, frequency of treatment, duration of treat-ment, and use of laboratory monitoring. Withoutdata to support treatment recommendations andlimited experience with the use of these agents,patient counseling becomes difficult, especially be-cause most tumors eligible for intralesional chemo-therapy have already presented managementdilemmas. By summarizing the literature, this com-prehensive review may help clinicians use intrale-sional chemotherapy to treat SCC, KA, and BCC withgreater confidence and safety.

METHODSA search of the MEDLINE database (1950-present)

was conducted to identify original studies evaluatingintralesional chemotherapy agents as the main ther-apy of nonmelanoma skin cancer (NMSC). The terms‘‘squamous cell carcinoma,’’ ‘‘basal cell carcinoma,’’‘‘keratoacanthoma,’’ ‘‘fluorouracil,’’ ‘‘methotrexate,’’‘‘bleomycin,’’ and ‘‘interferon’’ were used in

689

Page 2: Intralesional chemotherapy for nonmelanoma skin cancer: A practical review

J AM ACAD DERMATOL

OCTOBER 2010

690 Kirby and Miller

combination. Additional primary sources were iden-tified in the reference lists of articles identified by theMEDLINE search. More than 2500 articles wereidentified.

Sources in the form of letters, reports, or formalstudies that reported on primary cutaneous SCC,BCC, or KA treated with intralesional administration

CAPSULE SUMMARY

d Intralesional chemotherapy is atherapeutic option for nonmelanomaskin cancers when a patient cannot orwill not undergo surgery; however, thesmall number of reported cases and lackof long-term follow-up and therapeuticguidelines make this an infrequentlyused option.

d Keratoacanthomas and basal cellcarcinomas and interferon andfluorouracil are the most frequentlyinvestigated nonmelanoma skin cancersand chemotherapeutics, respectively, instudies of intralesional chemotherapy.

d Systemic toxicity can occur withintralesional placement of thesechemotherapeutic agents. Toxicitydepends on the agent used, features ofthe regimen, and comorbidities of thepatient. Baseline and intermittentlaboratory monitoring is recommendedas a precaution for all patients.

d Few studies have assessed the long-termcure rates of intralesional chemotherapy,making it difficult to compare withstandard surgical modalities.

of MTX, 5FU, bleomycin, orinterferon and remarked onclinical outcome were in-cluded. Some articles in-cluded tumors that had beenpreviously reported. In theseinstances tumors were in-cluded only once. The re-maining articles wereexcluded for the followingreasons: the article was notavailable in English; the med-ication was administeredsystemically, parenterally, ortopically, rather than exclu-sively intralesionally; thera-peutic outcome was notreported; excision was per-formed before the use ofintralesional chemotherapy;and proprietary or experi-mental formulations of themedication were used thatare not currently or widelyavailable. Articles using elec-troporation or needleless in-oculator for drug deliverywere also excluded, becausethese methods of drug deliv-ery are notwidely used. In all,56 articles fulfilled the criteriaand were used for data

collection.

The following data were extracted from eacharticle and included in our review: treatment med-ication, number of patients, drug concentration,dose per treatment, frequency of treatments, totaldosage, number of cancers with complete remission,length of follow-up, side effects, laboratory moni-toring, and if pretreatment or posttreatment biopsieswere performed. Characteristics of the tumors werealso collected, including type of cancer (KA, BCC,SCC), location, and size. Histologic subtype of BCCwas recorded whenever possible. It was also re-corded when posttreatment cure rates were deter-mined by clinical appearance or biopsyconfirmation. Complete response (CR) rates werecalculated using all tumors reported to be cured,

whether biopsy proven or not, divided by thenumber of tumors treated.

In the event that a patient with multiple NMSC wasreportedwithout details of the individual tumors, thenthe whole report was recorded as a single case.However, if the characteristics of individual lesionswere reported, then each individually described tu-

mor was counted separately.

RESULTSOf the 56 articles included

in our review, 51 of the sour-ces were case reports, caseseries, or open-label studies.Four were prospective, dose-comparison studies and onewas a randomized, placebo-controlled trial. Tables I to IVorganize these references anddata according to the intrale-sional agent.

Medicationadministration

Many authors used a 26-or 30-gauge 3/8-in needle ona tuberculin syringe to injectthe medication. Of the 56references, 28 described themethod of medication inoc-ulation; 3 methods were themost commonly used. Onemethod used tangential in-jection of 4 equal aliquots ofmedication into the quad-rants of the surface of thetumor and a fifth injectioninto the base. A secondmethod deposited the medi-

cation via multiple injections at the periphery, withor without an injection into the base. The thirdmethod injected at one or two sites of the tumor untilthe dermis blanched or a peau d’orange effect wasseen. Multiple authors noted a loss of up to 30% to50% of the volume of the injection flowing from thesurface of the tumor, particularly when treatingfriable KA or SCC.2-4

MethotrexateEight references report the use of intralesional

MTX to treat KA.2,4-10 There are no reports of its useon SCC or BCC. Six articles reported the treatment of36 tumors (Table I). Two sources reported adverseevents without remarking on clinical outcome, sowere not included.7,9 In all, 26 (72%) of the tumors

Page 3: Intralesional chemotherapy for nonmelanoma skin cancer: A practical review

Tab

leI.

Intr

ale

sio

nal

me

tho

tre

xate

Refe

ren

ces

Ty

pe

of

stu

dy

Tu

mo

r

typ

e

No

.o

f

tum

ors

/

pati

en

ts

Tu

mo

r

dia

mete

r/

mean

,cm

Dru

g

co

ncen

trati

on

,

mg/m

L

Do

se/

mean

No

.o

f

treatm

en

ts/

mean

Tre

atm

en

t

freq

uen

cy

/

mean

,d

To

tal

do

se/m

ean

,

mg

Cu

rera

te

Len

gth

of

foll

ow

-up

/

mean

,m

o

An

ne

ste

tal

,22

00

7C

ase

seri

es

KA

18

/18

1.0

-3.5

/2.1

12

.5o

r2

5N

R1

-3/2

12

-38

/22

1.8

75

-87

.5/3

61

5/1

8(8

3%

)1

-91

/23

Cu

est

a-R

om

ero

and

de

Gra

do

-Pe

na,

61

99

8C

ase

seri

es

KA

6/6

1.0

-2.8

/1.8

25

NR

/40

mg

1-4

/2.4

NR

12

.5-6

2.5

/33

.36

/6(1

00

%)

10

-20

/13

Co

he

ne

tal

,10

20

05

Cas

ere

po

rtK

A1

/1N

RN

RN

R3

14

19

.51

/1(1

00

%)

NR

Me

lto

ne

tal

,41

99

1C

ase

seri

es

KA

9/9

1.0

-3.0

/1.8

12

.5-2

5N

R1

-2/1

.71

45

-50

/21

.99

/9(1

00

%)

1-3

5/1

5d

eV

issc

he

re

tal

,82

00

2C

ase

rep

ort

KA

1/1

3.5

25

37

.5m

g2

14

75

1/1

(10

0%

)4

8Sp

ieth

et

al,5

20

00

Cas

ere

po

rtK

A1

/12

55

mg

57

25

1/1

(10

0%

)1

To

tal:

36

/36

Ave

rag

e:

1.9

8A

vera

ge

:1

2m

gA

vera

ge

:2

.2A

vera

ge

:3

3.8

To

tal:

33

/36

(91

.7%

)A

vera

ge

:1

9.5

KA

,K

era

toac

anth

om

a;N

R,

no

tre

po

rte

d.

J AM ACAD DERMATOL

VOLUME 63, NUMBER 4

Kirby and Miller 691

were on the face, scalp, or ears; 5 (14%) on the hand;4 (11%) on the leg; and one (3%) on the chest. Of thetumors, 24 (67%) were biopsy proven.

Of the 36 tumors treated, a cure was definedclinically in 33 (91.7%). Posttreatment biopsy wasdone in two (5.5%) cases. Although not specified forall cases, clinical follow-up ranged from 1 to 91months, with an average of 19.5 months. No recur-rences were noted. Laboratory monitoring (Table V)throughout the therapeutic period was performedfor one case and revealed normal findings.6 Twocases of pancytopenia after one dose of intralesionalMTX were reported in two patients with end-stagerenal disease on hemodialysis.7,9

5-FluorouracilNine articles reported the use of 5FU on 82

KAs.11-19 Three articles reported the use of 5FU in23 BCCs.12,20,21 Table II summarizes the data fromthese 12 studies. In all cases 5FU was administeredundiluted in a concentration of 50 mg/mL.

At least 68 KAs were treated; 26 of the tumors werelocated on the arm or hand, 24 were on the head orneck, and 3 were on the leg. Pretreatment biopsieswere performed on 13 tumors: 10 solitary KAs and asingle representative lesion on 3 patients with mul-tiple tumors. In all, 67 (98.5%) tumors were consid-ered clinically cured. The one tumor that did notrespond was reported by Odom and Goette.16 TheKA was located on the earlobe and did not involuteafter 5 treatments; subsequent excision removed thetumor and confirmed the diagnosis of KA.Posttreatment biopsies were done in 4 patients.16-18

Some cases have been followed up for as long as 24months or more without recurrence.12 Laboratorytesting (Table V) was done in 6 patients without anyabnormal finding.13,16

Three articles reported the use of 5FU in 23BCCs. One tumor was excluded because topical5FU was used immediately before intralesional usefor a BCC.12 This case was also reported twice: oncein a larger series and once as a case report todescribe the diagnosis of SCC in a persistent papuleat the BCC treatment site.20 All of the tumors werelocated on the head and neck. Tumor size was notreported for most cases. All tumors were biopsyproven. Histologic subtype of the BCC, whenreported, was infiltrative, superficial, or nodu-lar.12,21 The BCCs were recurrent in 3 cases andpreviously treated singly or serially with surgery,5FU ointment, or radiograph therapy.21 Of theBCCs, 23 (100%) were clinically cured with intrale-sional 5FU. Four of the sites had posttreatmentbiopsy results that confirmed a cure.12,21 Durationof follow-up was not noted. No recurrences were

Page 4: Intralesional chemotherapy for nonmelanoma skin cancer: A practical review

Table II. Intralesional fluorouracil

References

Tumor

type

Type of

study

No. of

tumors/

patients

Tumor

diameter

/mean, cm

Drug

concentration,

mg/mL

Dose/

mean,

mg

No. of

treatments

/mean

Treatm nt

freque cy/

mean d

Total

tumoral

dose/mean,

mg Cure rate

Length of

follow-up

/mean, mo

Kurtis andRosen,12 1980

BCC Case series 2/2 1.7-2.9/NR 50 NR 5-6/5.5 3 500-725/612.5 2/2 (100%) NR

Avant andHuff,21 1976

BCC Case series 21/3 NR 50 50-150/NR 4-8 3-14/N NR 21/21 (100%) NR

Total: 23/5 Total: 23/23(100%)

Kurtis andRosen,12 1980

KA Case series 3/3 0.8-1.3/1.0 50 NR 6-12/8.3 3 177.5-585/354 3/3 (100%) NR

Goette andOdom,15 1980(includespatients fromOdom andGoette,16 1978)

KA Case series 41/30 NR 50 NR; range,40-75

NR/3 7 NR 40/41 (97.5%) 1-22/NR

Klein et al,17 1962 KA Case series 2/2 NR 50 5 7-34/20 0.5-2/ 25 3.5-170/86.75 2/2 (100%) NRSingal et al,11 1997 KA Case report Numerous/1 0.1-2 50 10-15 3 7 30-45/NR Numerous

(100%)NR

Leonard andHanke,14 2006

KA Case report 1/1 4 50 NR 8 7-14/N NR 1/1 (100%) 9

Eubanks et al,19 1982 KA Case report 14/1 0.4-1.1 50 10-20/NR 5-9/NR 7 NR 14/14 (100%) 6Parker and

Hanke,13 1986KA Case series 5/4 2.2-6.0 50 50-150/NR 2-5/3.8 7-28/N 100-600/360 5/5 (100%) 18-45/30

Morse et al,18 2003 KA Case report 1/1 3.3 50 40-120/80 8 7 680 1/1 (100%) 5Total: $ 93/57 Average: 341 Total: 87/68

(98.5%)

BCC, Basal cell carcinoma; KA, keratoacanthoma; NR, not reported.

JA

MA

CA

DD

ER

MA

TO

L

OC

TO

BER

20

10

692

Kirb

ya

nd

Miller

e

n

,

R

1.

R

R

Page 5: Intralesional chemotherapy for nonmelanoma skin cancer: A practical review

Tab

leII

I.In

tral

esi

on

al

ble

om

ycin

Refe

ren

ces

Tu

mo

r

typ

e

Ty

pe

of

stu

dy

No

.o

f

tum

ors

/pati

en

ts

Tu

mo

r

dia

mete

r

/mean

,cm

Dru

g

co

ncen

trati

on

,

mg/m

L

Do

se/

mean

,

mg

No

.o

f

treatm

en

ts

/mean

Tre

atm

en

t

freq

uen

cy

/mean

,d

To

tal

do

se/m

ean

,

mg

Cu

re

rate

Len

gth

of

foll

ow

-up

/mean

,m

o

de

laT

orr

ee

tal

,23

19

97

KC

MC

ase

rep

ort

1/1

70

.50

.43

71

.21

/1(1

00

%)

48

An

dre

assi

et

al,2

41

99

9K

AC

ase

rep

ort

1/1

20

.50

.22

70

.41

/1(1

00

%)

18

Saya

ma

and

Tag

ami,2

21

98

3K

AC

ase

seri

es

6/6

0.7

-1.9

0.5

0.1

-0.4

/0.2

51

-2/1

.57

-14

/9.3

0.1

-0.8

/0.3

86

/6(1

00

%)

0.5

-3/N

R

To

tal:

8/8

Ave

rag

e:1

.98

Ave

rag

e:0

.3A

vera

ge

:1.7

5A

vera

ge

:0.6

48

/8(1

00

%)

Dya

ll-Sm

ith

,27

19

98

SCC

isC

ase

rep

ort

1/1

2.3

0.5

NR

72

1-4

23

.17

51

/1(1

00

%)

48

Mis

him

aan

dM

atu

nak

a,2

61

97

2B

CC

Cas

ese

rie

s3

/3N

R0

.2N

R4

-20

/NR

NR

NR

3/3

(10

0%

)3

-24

/NR

Gyu

rova

et

al,2

52

00

6B

CC

Cas

ere

po

rt8

/1N

R0

.00

07

.00

02

57

20

.00

17

58

/8(1

00

%)

24

To

tal:

12

/5T

ota

l:1

2/1

2(1

00

%)

BC

C,

Bas

alce

llca

rcin

om

a;K

A,

kera

toac

anth

om

a;K

CM

,ke

rato

acan

tho

ma

cen

trif

ug

um

mar

gin

atu

m;

NR

,n

ot

rep

ort

ed

;SC

Cis

,sq

uam

ou

sce

llca

rcin

om

ain

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om

ycin

con

vers

ion

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=1

50

0IU

=2

U(U

SP).6

0

J AM ACAD DERMATOL

VOLUME 63, NUMBER 4

Kirby and Miller 693

reported. Laboratory monitoring was not done inany study.

BleomycinIntralesional bleomycin was reported in 3 studies

for the treatment of KA,22-24 two studies forBCC,25,26 and one case report described the treat-ment of SCC in situ (SCCis).27 Of the 6 total studies(Table III), 5 administered the bleomycin diluted 1:1with an anesthetic (lignocaine, lidocaine, orMarcaine) to minimize pain associated with theinjections.22-25,27

Three studies reported 8 KAs treated with intra-lesional bleomycin.22-24 Six (75%) of the tumorswere on the face, one (12%) on the arm, and one(12%) on the leg, which was characterized as a KAcentrifugum marginatum. All 8 (100%) of the KAswere considered clinically cured and none hadposttreatment biopsies. The tumors were followedup for 2 weeks to 4 years, with an average observa-tion period of 9 months and there were no reportedrecurrences.

Intralesional bleomycin has also been used totreat 11 BCCs on 4 patients in two case reports.25,26

Ten (91%) tumors were located on the face or ear andone (9%) tumor was on the back. Pretreatmentbiopsy was done on at least 9 (82%) of the BCCs.All 11 (100%) were considered clinically cured andnone had a posttreatment biopsy. The patients werefollowed up for 3 to 48 months without a reportedrecurrence. Laboratory monitoring (Table V) wasdone in one patient treated for 8 tumors and noabnormal findings were reported.25

InterferonInterferon alfa-2, -2a, and -2b, and the combina-

tions of these have been administered intralesionallyto treat BCC, SCC, and KA. Intralesional interferonbeta and gamma have been used to treat BCC.28-31

Table IV summarizes the characteristics of the studiesusing intralesional interferon.

BCC and interferon alfaInterferon alfa-2a was used to treat BCC in 5

reports on 66 tumors.32-36 The tumors were locatedon the head and neck in 63 (95%) of the patients;the 3 (5%) remaining tumors were on the trunk. Alltumors had a pretreatment biopsy. Nine (14%) ofthe tumors had an infiltrative or morpheaformgrowth pattern, whereas the remaining tumorshad a nodular, ulcerative, or superficial growthpattern. The dose was determined by the size ofthe tumor in 55 (83%) of the tumors. All treatmentsites had a posttreatment assessment; biopsieswere performed on 51 (77%) sites and a superficial

Page 6: Intralesional chemotherapy for nonmelanoma skin cancer: A practical review

Table IV. Intralesional interferon

References

Tumor

type

Interferon

type

Type of

study

No. of

tumors/

patients

Tumor

diameter/

mean

Drug

concentration,

mU/mL

Dose/

mean,

mU

No. of

treatments/

mean

Treatment

frequency/

mean, d

Total

dose/

mean, mU

Cure

rate

Length of

follow-up/

mean, mo

KA and interferon

Wickramasinghe

et al,51 1989

KA Interferon

alfa-2

Open-label trial 1/1 NR 3 0.9 9 TIW 8.1 1/1 (100%) 3

Grob et al,55 1993 KA Interferon

alfa-2a

Open-label trial 6/6 2-3.5 cm NR 2-6/5 9-20/12 TIW 24-117/57 6/6 (100%) 6-36/18

Oh et al,56

2004

KA Interferon

alfa-2b

Case series 4/4 1.6-2.1/1.8 cm 3 3 4-6/5 7 12-18/15 4/4 (100%) 19-27/24.5

Total: 11/11 Average: 3.8 Average: 9 Average: 37.3 Total: 11/11

(100%)

SCC and interferon

Wickramasinghe

et al,51 1989

SCC Interferon

alfa-2

Open-label

trial

3/3 NR 3 0.9 9 TIW 8.1 3/3 (100%) 3

Edwards et al,53

1992

SCC,

SCCis

Interferon

alfa-2b

Open-label

trial

34/34 0.5-2 cm 10 1.5 9 TIW 13.5 33/34 (97%) 3

Kim et al,47

2004

SCC,

SCCis

Interferon

alfa-2b

Case series 3/3 NR NR 2-2.5/2.2 9-12/10 TIW 18-30/22 3/3 (100%) 23-42/30

Total: 40/40 Average: 1.5 Average: 9 Average:

SCC = 13;

SCCis = 15

Total: 39/40 (98%)

BCC and interferon alfa

Wickramasinghe

et al,51 1989

BCC Interferon

alfa

Open-label trial 11/11 NR 3 0.9 9 TIW 8.1 1/11 (9%) 3

Greenway

et al,52 1986

BCC Interferon

alfa

Open-label trial 6/6 0.7-1.4 cm 10 1.5 9 TIW 13.5 6/6 (100%) 2

LeGrice et al,33

1995

BCC Interferon

alfa-2a

Open-label trial 11/11 0.5-2 cm NR 1.5 9 TIW 13.5 8/11 (73%) 13-18/NR

Bostanci et al,36

2005

BCC Interferon

alfa-2a

Open-label trial 20/13 Area: 0.3-7 cm2 NR \2 cm2: 1.5;

[2 cm2: 3

9 TIW 13.5 or 27 11/20 (55%), 8/11

CR were \2

cm2

84, 1 Recurrence

Dogan et al,32

1995

BCC Interferon

alfa-2a

Open-label trial 13/13 Area: 0.2-6 cm2 NR \0.6 cm2: 3; 0.6-2

cm2: 4.5

12 TIW 36 or 54 11/13 (85%), 4/4

CR were

\0.6 cm2

12

Grob et al,34 1988 BCC Interferon

alfa-2a

Open-label trial 8/7 3-35/11 cm2 NR \2 cm2: 1.5; 2-12

cm2: 4.5;

[12 cm2: 6

18-33/23 TIW 24-156/74.6 8/8 (100%) 3-8/5

Alpsoy et al,35

1996

BCC Interferon

alfa-2a

Open-label trial,

randomized

15/15 Area: 0.5-8.75 cm2 NR \2 cm2: 1.5; [2

cm2: 3

10 TIW 15 or 30 10/15 (67%) 2

Kim et al,47

2004

BCC Interferon

alfa-2b

Case series 3/2 NR NR 1-2/1.5 9 TIW 9-18/13.5 3/3 (100%) 22-23/22.7

Mozzanica et al,40

1990

BCC Interferon

alfa-2b

Open-label trial 6/6 1.5-3.0 cm 3 1.5 9 TIW 13.5 2/6 (33%) 2

McDonald and

Georgouras,48

1992

BCC Interferon

alfa-2b

Case report 3/1 Area: 1.5-5.4 cm2 3 \2 cm2: 1.5; 2-12

cm2: 4.5

8-18/14 TIW 24-54/43 3/3 (100%) 20, 1 Recurrence

Tucker et al,49

2006

BCC Interferon

alfa-2b

Case series 98/98 NR 5 1.5* 9 NR 13.5y 67/69 (97%) 84

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Chimenti

et al,45 1995

BCC Interferon

alfa-2b

Open-label trial 140/140 0.3-5 cm NR \2 cm2: 1.5;

[2 cm2: 3

12-24/NR TIW NR 94/140 (67%) 12-54/36

Thestrup-

Pedersen

et al,46 1990

BCC Interferon

alfa-2b

Open-label trial 10/10 0.7-1.9 cm NR 1.5 9 TIW 13.5 6/10 (60%) 3-21/14

Pizarro and

Fonseca,38

1994

BCC Interferon

alfa-2b

Open-label trial 25/25 0.5-2 cm 3 1.5 9 TIW 13.5 19/25 (76%) 12-38/24

Boneschi

et al,39 1991

BCC Interferon

alfa-2b

Open-label trial 27/27 \3 cm 10 1.5 9 TIW 13.5 14/27 (52%) 2-12/NR

Buechner,41

1991

BCC Interferon

alfa-2b

Open-label trial 4/4 NR 5 1.5 6 TIW 9 4/4 (100%) 1

Kopera et al,42

1996

BCC Interferon

alfa-2b

Case report 3/1 NR NR 1.5 9 TIW 13.5 0/3 (0%) NR

Healsmith

et al,43 1991

BCC Interferon

alfa-2b

Open-label trial 10/10 0.5-2 cm NR 1.5 9 TIW 13.5 6/10 (60%) 12-26/17

Stenquist

et al,44 1992

BCCz Interferon

alfa-2b

Open-label trial 15/15 0.7-2.5 cm 10 1.5 9 TIW 13.5 4/15 (27%) 2

Cornell et al,50

1990

BCC Interferon

alfa-2b

Randomized

placebo

controlled trial

Interferon: 120;

placebo: 42

0.5-1.5,

0.5-2 cm for

superficial

10 1.5 or placebo 9 TIW 13.5 Interferon:

103/120 (86%);

placebo: 12/42

(29%)

12, 7 Recurrences

Alpsoy et al,35

1996

BCC Interferon

alfa-2b

Open-label trial,

randomized

15/15 Area: 0.6-8.2 cm2 NR \2 cm2: 1.5;

[2 cm2: 3

10 TIW 15 or 30 10/15 (67%) 2

BCC and interferon beta

Kowalzick

et al,28 1994

BCC Interferon

beta

Open-label trial 69/69 0.5-2 cm 9.6 or 19.2 0.5, 1.0, 3.0/1.3 3, 6, 9/6.6 7, 3, TIW 2.2 3-18/7.7 35/69 (50%),

range, 14%-

86%

3, 4 Recurrences

Kowalzick

et al,29 2002

BCC Interferon

beta

Open-label trial 133/133 0.5-2 cm NR 1 9 TIW 9 89/133 (67%) Median = 24,

1 recurrence

Total: 202/202 Average: 9.9 Total: 124/202

(61%)

BCC and interferon gamma

Edwards et al,31

1990

BCC Interferon

gamma

Open-label,

randomized

trial

29/29 Nodular: 0.5-2 cm;

superficial:

# 3 cm

2 0.02 9 TIW 0.18 1/14 (7%) 3

10 0.1 9 TIW 9 7/14 (50%)

Tank et al,30 1989 BCC Interferon

gamma

Open-label trial 7/7 0.8-2.2 cm 2 0.02 8 3 0.16 0/7 (0%) 2

Total: 36/36 Average: 0.025 Average: 0.23 8/35 (22%)

BCC, Basal cell carcinoma; CR, complete response; KA, keratoacanthoma; NR, not reported; SCC, squamous cell carcinoma; SCCis, squamous c ll carcinoma in situ; TIW, 3 times weekly on alternate

days.

Study on sustained release Interferon alfa-2b formulation not included.

*Large tumors were divided into 2-cm2 areas and each area was serially treated with 9 injections of 1.5 mU.yLarge tumors received higher cumulative dose because of serial treatments (see above).zAll BCC were recurrent tumors or primary morpheaform type.

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Table V. Medication mechanisms, contraindications, monitoring, and cost

Medication:

Mechanism of action Contraindication/cautious use Laboratory monitoring Side effects Cost

Methotrexate:Antagonist of folatemetabolism, inhibits DNAsynthesis

Renal insufficiency or hemodialysis;liver disease or cirrhosis;pregnancy or breast-feeding;concomitant use of: probenecid,penicillin, trimethoprim,sulfonamides, dapsone,salicylates, sulfonylureas, NSAIDs,dipyridamole, phenothiazines,phenytoin, tetracyclines, alcohol,systemic retinoids

Baseline: CBC diff, LFT, BUN, CrBefore subsequent treatments:

CBC diff (LFT not needed becauseliver disease is associated withchronic use)

Local: pain, erythema, crusting,ulceration, necrosis

Systemic: cytopenias, pulmonaryfibrosis, gastrointestinal upset,diarrhea, stomatitis,hepatotoxicity, nephrotoxicity,teratogenicity

$25/250 mg (10 mL)

Fluorouracil: Antimetaboliteand structural analogof uracil, disrupts DNA andRNA synthesis

Liver disease; pregnancy or breast-feeding; allergy to medication;maximum daily recommendeddose: 800 mg

Baseline: CBC diffWeekly: CBC diff

Local: pain, erythema, crusting,ulceration, necrosis

Systemic: cytopenias,gastrointestinal upset

$26/250 mg (50 mL)

Bleomycin:Cytotoxic by damaging DNA

Pregnancy, breast-feeding Baseline: CBC diffWeekly: CBC diff

Local: pain, erythema, crusting,ulceration, necrosis

Systemic: pulmonarytoxicity, Raynaudphenomenon, skin sclerosis

$350/15-mg vial

Interferon (alfa, beta, or gamma):Antiproliferative andimmunoregulatory

Renal insufficiency or hemodialysis;liver disease; pregnancy, breast-feeding; autoimmune disease;hematopoietic disease; avoidconcomitant use of NSAIDs*

Baseline: CBC diff, BUN, Cr, LFTWeekly: CBC diff, BUN, Cr, LFT

Local: pain, erythema, crusting,ulceration, necrosis

Systemic (dose-dependent): fever,malaise, myalgias, headache,emotional lability, alopecia,nausea, cytopenias,hepatotoxicity, nephrotoxicity

$395/22.8-mU vialinterferon alfa-2b

$2175/4-mU vialinterferon beta

BUN, Serum urea nitrogen; CBC diff, complete blood cell count with differential; Cr, creatinine; LFT, liver function tests; NSAID, nonsteroidal anti-inflammatory drugs.

*Concomitant use of NSAIDs may interfere with antitumor effects. Acetaminophen was used for treatment of flu-like symptoms.

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Tab

leV

I.C

om

par

iso

no

fcu

rera

tefo

rsu

rgic

alm

od

alit

ies

and

intr

ale

sio

nal

the

rap

y

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mo

rIn

terf

ero

nalf

a-2

a

Inte

rfero

n

alf

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terf

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nb

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rfero

n

gam

ma

Meth

otr

ex

ate

Flu

oro

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Ble

om

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hs

mic

rogra

ph

ic

surg

ery

Ex

cis

ion

BC

CSu

bg

rou

ps

wit

hh

igh

est

cure

rate

s*

68

%(4

5/6

6)

10

0%

(8/8

)34

76

%(3

63

/47

9)

98

%(9

6/9

8)4

96

8%

(12

8/2

02

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)28

22

%(8

/36

)5

0%

(7/1

4)3

19

6%

(23

/24

)1

00

%(1

1/1

1)

99

%5

79

0%

57

SCC

SCC

is9

0%

(28

/31

)8

9%

(10

/11

)1

00

%(1

/1)

97

%5

79

2%

57

KA

91

%(1

0/1

1)

92

%(3

3/3

6)

98

%(5

4/5

6)

10

0%

(8/8

)9

8%

-10

0%

59

92

%5

9

BC

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llca

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om

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A,

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C,o

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stan

tial

lyb

ett

er

cure

rate

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ano

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nb

eco

nsi

de

red

.

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Kirby and Miller 697

scraping was done on 15 (23%) sites. CR occurredin 45 (68%) of the tumors. The CR for all BCCslarger than 2 cm2 was 73% (16/22) whereas the CRimproved slightly to 76% (16/21) when these largertumors were treated with a higher dose based ontheir size.32-34,36 The duration of follow-up rangedfrom 3 months to 7 years, with an average of 18months. There was one (1.5%) recurrence.36 Somepatients took acetaminophen at the time of treat-ment.35 Patients were asked to avoid nonsteroidalanti-inflammatory drugs in all studies. Laboratorytesting (Table V) was done at baseline and duringthe treatment course for all of the patients.Elevated liver function tests were reported in onepatient.35 None of the patients stopped therapybecause of side effects or changes in laboratoryresults.

Fifteen articles discuss the use of interferon alfa-2b for the treatment of 542 BCCs.35,37-50 Of these, 65were treated in a study using a sustained-releaseformulation of interferon alfa-2b and will be consid-ered separately.37 The remaining 477 tumors werelocated on the head and neck in 298 (62%) of thecases, on the trunk in 140 (30%), and on theextremities in 38 (8%). The location of one treatedtumor was not reported. Seven of the studies ex-cluded tumors larger than 2 or 3 cm in diameter andaccount for 302 (65%) of the tumors treated withinterferon alfa-2b. Overall, pretreatment biopsy wasperformed on 415 (87%) of the tumors. The histo-logic type of BCC included 161 (34%) superficialtumors, 256 (54%) nodular tumors, 29 (6%) ulcera-tive type, 22 (4%) infiltrative or morpheaform type,and 9 (2%) recurrent tumors. Four studies deter-mined the treatment dose based on the tumor size.For all studies, a CR was obtained in 76% (363).Seven of the studies followed up the patients for amedian time of at least 1 year and reported 6 (1.6%)recurrences. Laboratory monitoring (Table V) wasreported in 10 of the 15 articles. Reversible cytope-nias occurred in 30 patients and elevations (\3times) of liver function tests occurred in 9 patients.No patient discontinued treatment because of labo-ratory changes.

Individual studies treated BCC with a sustained-release formulation of interferon alfa-2b,37 the com-bination of interferon alfa-2a and -2b,35 or an olderformulation of interferon alfa-250,51 (not specificallyalfa-2a or -2b). First, sustained-release interferonalfa-2b was used on 65 patients; 63 patients com-pleted the study and two dropped out because ofsystemic side effects. One group of 33 tumors wastreated with one dose of 10 mU in a volume of0.2 mL; 17 (52%) were cured with histologic confir-mation. A second group of 30 tumors was treated

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Table VII. Most frequent characteristics of tumors and therapeutic regimens for keratoacanthoma and basalcell carcinoma

KA BCC

MTX 5FU Bleomycin* Interferon alfa-2a Interferon alfa-2b Interferon beta

Tumors cured/treated 33/36 (92%) 54/55 (98%) 8/8 (100%) 45/66 (68%) 363/489 (76%) 128/202 (63%)Diameter, cm 1.98 2.1 1.27 na na naDose 12 mg 40 mg 0.24 mg 2.6 mU 1.5 mU 1.1 mUTreatments 2.1 7.7 1.6 11.5 9 9Frequency 1-2 wk 1 wk 1 wk TIW TIW TIWTotal dose 33.8 mg 341 mg 0.36 mg 34 mU 13.5 mU 9.9 mU

BCC, Basal cell carcinoma; 5FU, 5-fluoruracil; KA, keratoacanthoma; MTX, methotrexate; na, not available; TIW, 3 times weekly.

*Excluding single case report of KA centrifugum marginatum.

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with 3 weekly doses of 10 mU; 24 (80%) were curedwith histologic confirmation.37

Alternating doses of interferon alfa-2a and -2b wereused on 15 BCCs. A CR was obtained in 11 (73%)patients after 3 times weekly dosing for 3 weeks.35

Thirdly, interferon alfa-2 was used in two stu-dies.51,52 BCCs were given 0.9 mU (11 tumors) or 1.5mU (8 tumors) 3 times weekly for 3 weeks (9 totaldoses). None of the tumors treated with the 0.9-mUdose had a cure. All 8 (100%) of the tumors treatedwith the 1.5-mU dose had a histologic CR. If alltumors treated with interferon alfa-2 and -2b areconsidered together, the overall CR decreases from76% to 74.5%.

SCC and interferon alfa. In all, 31 invasiveSCCs and 9 SCCis treated with interferon alfa-2 or -2bwere reported in 3 articles.47,51,53 The location of thetumors, when specified, was on the legs, hand/digit,ear, or other site with surrounding sun damage. Allcases had a pretreatment biopsy. A CR was achievedin 37 (92.5%) cases. The cure rate for invasive SCCand SCCis was 90% (28/31) and 89% (8/9), respec-tively. Posttreatment biopsies were done on all butone (3%) SCC and all but two (22%) SCCis. Twopatients treated for SCCis developed a second ma-lignancy; one patient developed a dermatofibromasarcoma protuberans 1 year later at a different siteand another patient was given a diagnosis of chroniclymphocytic leukemia 6 months later.54 Laboratorytesting (Table V) was done in 30 (75%) of thepatients. Seven had elevated liver function testresults and 3 had changes in their complete bloodcell count; none discontinued therapy and allchanges normalized 5 weeks after treatment.53 Sideeffects were not noted in those receiving the lowesttreatment dose of 0.9 mU51 but occurred in 65% ofthose receiving 1.5 mU per treatment.53

KA and interferon alfa. Three articles reportedthe use of interferon alfa-2, -2a, or -2b for treatment

of KA.51,55,56 Eleven tumors were treated: 10 (91%)on the head or neck and one (9%) on the back of thehand. Pretreatment biopsy was done on 8 tumors.The tumors were cured in 10 (91%) cases andconfirmed by posttreatment biopsies in 4 (36%)cases. One tumor was excised after 3 weeks becauseof lack of improvement. The individual CR forinterferon alfa-2, -2a, and -2b were 100% (1/1), 83%(5/6), and 100% (4/4), respectively. Follow-upranged from 6 to 36 months with an average of 20months and no recurrences were reported.Laboratory testing (Table V) was performed in 10(91%) patients and only one patient developedneutropenia, but did not discontinue therapy.55

BCC and interferon beta. Intralesional inter-feron beta has been used to treat 202 BCCs.28,29 Thesites of the tumors were not specified. Pretreatmentbiopsy was done in all patients. Morpheaform typesof BCC were excluded from the study. Nodular,superficial, and ulcerative subtypes of BCC wereincluded; the number of each was not specified ineither source. In all, 124 (61%) tumors had a CR andall but two were confirmed by posttreatment biopsy.Recurrences occurred in 5 tumors CR at 6 months(two), 1 year (two), and 2 years (one).28,29 Laboratorymonitoring (Table V) was done for all patients andnone had ‘‘significant’’ laboratory changes. The out-come was judged to be good to excellent and withoutscarring aside from prior biopsy sites.

BCC and interferon gamma. Interferon gammawas used in two studies to treat 36 tumors in as manypatients.30,31 One study did not report sites of thetumors; in the second study, 6 were on the head orneck and one was on the leg. Pretreatment biopsieswere done on all 36 (100%) tumors. In all, 21 (58%)were nodular and 15 (42%) were superficial; mor-pheaform BCC were excluded from both studies.Overall, CR occurred in 8 (22%) cases and 7 of thesewere treated with the highest dose regimen.31 The

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treatment site was excised 2 to 3 months after the endof treatment, so all CR were confirmed by pathology.Laboratory monitoring (Table V) was done in allpatients at baseline and during treatment and noabnormal findings were reported.

DISCUSSIONSurgery remains the mainstay of treatment of

invasive SCC and some BCC. For high-risk tumors,Mohs micrographic surgery is the standard of care,because of its consistently superior cure rates. Inselect circumstances, for example when excisionalmodalities have repeatedly failed or are not possible,the treatment of tumors with intralesional chemo-therapy may be a reasonable option (Table VI). Thelack of well-designed trials or guidelines for the useof intralesional chemotherapy leaves the clinicianwith little evidence to guide decisions on this mo-dality. By summarizing the literature, this compre-hensive review may help clinicians use intralesionalchemotherapy to treat SCC, KA, and BCC withgreater confidence and safety.

Clinicians may consider several variables whenselecting the ideal intralesional chemotherapy agent.The mechanisms of action, contraindications, side-effect profiles, recommended laboratory monitoring,and cost are summarized in Table V. Although thepotential systemic side effects can be serious, mostside effects from the drugs occur at the site ofinjection and are comparable among all the agents.

Choice of intralesional agent may depend on typeof tumor. KAs have been treated with MTX, 5FU,interferon alfa-2a, and bleomycin; however, MTXand 5FU have been used on more tumors than theother agents. The CR for MTX and 5FU were 92% and98%, respectively. Both therapies were administeredweekly in most cases and were well tolerated. In ouropinion, both MTX and 5FU are reasonable firstchoices for intralesional chemotherapy of KA.

SCC, both in situ and invasive, has been treatedwith interferon alfa-2a and bleomycin; however,only 43 tumors have been treated. Bleomycin wasused in a single case, so the true use of this agent isunknown. We believe further studies should beundertaken before it can be recommended.Interferon alfa-2a demonstrated a CR of 90% and89% for SCC and SCCis, respectively. This is not verydissimilar to the 92% CR rate of conventional exci-sion.57 Flu-like symptoms occurred in many patientsgiven intralesional injections and patients should becounseled regarding this effect.

BCC represents the majority of tumors treated withany type of intralesional chemotherapy. Interferonalfa-2a, alfa-2b, beta, and gamma; 5FU; andbleomycinhave been reported. The CR of the interferons (alfa,

beta, or gamma) are all inferior to the CR of conven-tional excision and Mohs micrographic surgery(Table VI). Subgroups of tumors treated with inter-feron demonstrated better efficacy than the overallgroup. Interferons alfa-2a, alfa-2b, beta, and gammahave shown CR as high as 100%, 98%, 84%, and 50%,respectively. Because these were subgroups, a smallernumber of BCC were treated: 8 with interferon alfa-2a,98 with interferon alfa-2b, 14 with interferon beta, and14 with interferon gamma. Bleomycin and 5FU havebeen used on fewer BCC than interferon. Eleventumors were treated with bleomycin and 24 with 5FU,resulting in a CR of 100% and 96%, respectively. Theserates of clearance are better than those reported withconventional excision and not very dissimilar fromthose reported after Mohs micrographic surgery.57

Although the sample size is small with these agents,the CR is impressive. Further study is worthwhile andthe use of bleomycin and 5FU could be considered inpatients not amenable to surgery.

High-risk histologic subtypes of BCC such asmorpheaform, infiltrative, or recurrent tumors wereoften excluded from the studies. Six reports didinclude these types of BCC; interferon alfa-2a wasused in 3 reports and interferon alfa-2b was usedin 4. One study used interferon alfa-2a, -2b, orboth.34-36,38,44,47 Dose and frequency of interferonwas similar to the majority of BCC treated withthese agents. A total of 37 tumors were treated: 7with interferon alfa-2a, 28 with interferon alfa-2b,and two with the combination of interferon alfa-2aand -2b; the CR was 100%, 54%, and 50%, respec-tively. Long-term follow-up was not reported. Incontrast, Mohs micrographic surgery can deliver 5-year relapse-free survival in 94% of cases for thesesame types of BCC.58 We recommend interferontherapy for high-risk subtypes of BCC only whenMohs micrographic surgery is not an option.

Multiple methods of depositing the drug havebeen described, and there have been no studies toassess the efficacy of the method of drug delivery. Ingeneral, injections are placed strategically to infiltratethe periphery and base of the tumor.21,37,53 Blanchingof the tumor and a peau d’orange change serve asclinical markers for effective infiltration. Large ormultiple tumors may require a volume of medicationthat approaches the maximum recommended dose.In these instances, segmental treatment (of a 2-cm2

portion at a time) using the drug regimens suggestedabove for smaller tumors is an option.

Tumor dose and frequency of injection varywidely. Some studies used size-based doses; multi-ple studies used 2 cm2 as the threshold to determineif a tumor smaller or larger would receive a lower orhigher dose, respectively.32,34-36,45,48 The frequency

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and number of injections is also not standardized.Some authors followed up the treatment protocoluntil the tumor became crusted, friable, and/orulcerated then allowed the area to heal beforeresuming injections.13,21 By contrast, several authorscontinued regular treatment even if the lesion wasnecrotic.3,11,14,16,18,19 In general, frequency andnumber of injections was determined by tumordestruction, reduction in size, or both.

Local side effects are similar with each of the 4agents examined. Injections of 5FU or bleomycin arereported to be more painful, so it is common topretreat with intralesional anesthetic.12-14,20-22,24,27 Incontrast, local anesthesia is not used when adminis-tering MTX or interferon. There have been no studiesto determine the potential for dilution or alteration ofeffect when anesthetic is used. Intralesional admin-istration caused some degree of pain, erythema,crusting, ulceration, necrosis, or a combination ofthese. These site-limited reactions were often welltolerated and very few patients discontinued therapyfor this reason.

Potential systemic adverse effects of each medica-tion are listed in Table V. Systemic side effects with allof these medications are more common when theyare administered parenterally, but intralesional ad-ministration does not eliminate the risk. Monitoringblood work was performed in the minority of studies,but done most consistently in those administeringinterferon. Of the 127 tumors treated with MTX, 5FU,or bleomycin, only 8 patients had monitoring bloodwork performed starting at baseline through the endof treatment. None of these patients had abnormalfindings requiring discontinuation. Two patients onhemodialysis treated with MTX for KA developedpancytopenia and discontinued therapy. Laboratorymonitoring was not planned in either patient but wasdone after they developed hemorrhagic skin lesions.In comparison, 923 tumors in 28 studies were treatedwith interferon alfa, beta, or gamma and 22 of thestudies required laboratory monitoring. Reversiblelaboratory changes, most commonly cytopenias,were reported but none necessitated discontinuationof the medication. The absence of evidence demon-strating risk does not equal the absence of risk so it isrecommended that baseline and monitoring bloodwork be performed.

Cure rates were most often clinically determinedand posttreatment biopsies were not done in manystudies. Cure rates for each drug are summarized inTable VI. Clinical CR would likely overestimate thetrue CR because occult tumor would not be iden-tified. When performed, posttreatment biopsieswere performed either soon or delayed from theend of treatment. A delay in performance of a

posttreatment biopsy may have allowed for furtherresolution of the tumor or vice versa allowed forresolution of an inflammatory infiltrate that couldobscure residual tumor. Many patients had follow-up periods of less than a year; however, some werefollowed up for longer. A short follow-up periodwould contribute to inflation of the efficacy ofintralesional chemotherapy.

The cosmetic outcomes were similar with all typesof intralesional chemotherapy. None of the studiesused a formal method to grade outcomes by inves-tigators or patients. Outcomes were often brieflyreported in the ‘‘Discussion’’ section if they weredescribed at all. Trends for cosmetic outcomes bytype of medication or type of tumor could not bedetermined because of the lack of detail in theprimary sources. Overall, authors rated cosmeticoutcomes as good or excellent and with minimal tono scarring. Small scars from pretreatment biopsieswere noticed in some patients. Some sites wereslightly depressed after treatment and may havebeen a result of either the effects of the medicationor tissue destruction by the tumor.34 Pigmentarychanges, such as hypopigmentation or hyperpig-mentation, were not uncommon.3,4,12,21,25,51,55,56

Authors did not report if these changes improvedat subsequent follow-up visits. Patients with large KAhad some destruction of normal tissues with subse-quent clefting or notching and required surgery forcosmetic reconstruction.14,55 Two patients devel-oped milia at the treatment site after MTX for aKA.34 No additional reports of milia at a treatment sitewere found. In summary, it is reasonable to counselpatients of the risk of scarring that may occur frompretreatment and posttreatment biopsies and fromthe intralesional therapy. For the reported cases,scars were slight to absent and when present werethe same size or slightly smaller than the tumor.Postinflammatory erythema or dyspigmentationwould be present initially but improve or resolvewith time. Other drug-specific side effects such asserpentine hyperpigmentation associated with intra-venous use of 5FU or flagellate hyperpigmentationwith bleomycin has not been reported with theintralesional treatment of NMSC.

Limitations of this review include those of theprimary sources reviewed: the primary sources wereoften case reports or small case series so a smallnumber of patients were treated; selection bias mayhave favored patients thought to be responders or,conversely, patients with advanced disease; investi-gators were not blinded; and posttreatment biopsieswere not consistently performed so the reported CRmay not be reflective of the true effect. In an effort toinclude as many cases as possible in this review,

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some patients with multiple tumors were counted asonly one case because sufficient detail of each tumorwas not included. This would underestimate the trueeffect of treatment when all lesions are cured.Reports of failures are less likely to be reported andpublished in the literature and therefore wouldinflate the CR of these agents. Follow-up for manyof these studies was limited to 12 to 18 months; rarelywas there observation for 5 years, which is anaccepted threshold for the efficacy of a cancertreatment. One study reported follow-up after 15years for 98 BCCs treated with interferon alfa-2b.49

The 5-year success rate was 98%, with only two (2%)recurrences. The recurrences occurred at the sites ofBCC on the nose and face (other than the nose).

Based on the data collected, we conclude thatintralesional chemotherapy can be an effective andwell-tolerated treatment modality for NMSC (TableV). Care must be taken to chose tumors that areamenable, consider surgical modalities, and educatepatients as to expectations of the course of treatmentincluding local and systemic side effects, laboratorymonitoring, need for posttreatment biopsies, andclinical follow-up. Some combinations of type oftumor and chemotherapy agent are not well sup-ported (eg, SCC, SCCis, bleomycin) and more studiesare needed before these can be recommended. Ourfinal treatment recommendations include perform-ing pretreatment and posttreatment biopsies; per-forming pertinent laboratory monitoring at baseline,during treatment, and after treatment; using analternate treatment modality if the tumor grows orpersists unchanged after 2 to 3 weeks of treatment;and clinical observation for recurrence. Table VIIsummarizes the characteristics of the therapeuticregimens for KA and BCC, the tumors with themost evidence to support the use of intralesionalchemotherapy, and provides a possible startingpoint for treatment.

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