Intralesional chemotherapy for nonmelanoma skin cancer: A practical review

Intralesional chemotherapy for nonmelanoma skin cancer: A practical review Joslyn S. Kirby, MD,a and Christopher J. Miller, MDb 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 chemotherapy 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 guidelines 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 interferon solutions are labeled for intravenous or subcutaneous 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 chemotherapy leaves the clinician with little evidence to guide practical management decisions. The existing literature varies widely in choice of intralesional agent, method of intralesional administration, concentration of the medication, dose per From the Department of Dermatology, Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey,a and Department 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

Abbreviations used: BCC: CR: 5FU: KA: MTX: NMSC: SCC: SCCis:

basal cell carcinoma complete response 5-fluoruracil keratoacanthoma methotrexate nonmelanoma skin cancer squamous cell carcinoma squamous cell carcinoma in situ

treatment, frequency of treatment, duration of treatment, 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 because most tumors eligible for intralesional chemotherapy have already presented management dilemmas. By summarizing the literature, this comprehensive review may help clinicians use intralesional 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 therapy of nonmelanoma skin cancer (NMSC). The terms ‘‘squamous cell carcinoma,’’ ‘‘basal cell carcinoma,’’ ‘‘keratoacanthoma,’’ ‘‘fluorouracil,’’ ‘‘methotrexate,’’ ‘‘bleomycin,’’ and ‘‘interferon’’ were used in 689

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combination. Additional primary sources were idenwhether biopsy proven or not, divided by the tified in the reference lists of articles identified by the number of tumors treated. MEDLINE search. More than 2500 articles were In the event that a patient with multiple NMSC was identified. reported without details of the individual tumors, then Sources in the form of letters, reports, or formal the whole report was recorded as a single case. studies that reported on primary cutaneous SCC, However, if the characteristics of individual lesions BCC, or KA treated with intralesional administration were reported, then each individually described tuof MTX, 5FU, bleomycin, or mor was counted separately. interferon and remarked on CAPSULE SUMMARY clinical outcome were inRESULTS cluded. Some articles inOf the 56 articles included Intralesional chemotherapy is a cluded tumors that had been in our review, 51 of the sourtherapeutic option for nonmelanoma previously reported. In these ces were case reports, case skin cancers when a patient cannot or instances tumors were inseries, or open-label studies. will not undergo surgery; however, the cluded only once. The reFour were prospective, dosesmall number of reported cases and lack maining articles were comparison studies and one of long-term follow-up and therapeutic excluded for the following was a randomized, placeboguidelines make this an infrequently reasons: the article was not controlled trial. Tables I to IV used option. available in English; the medorganize these references and Keratoacanthomas and basal cell ication was administered data according to the intralecarcinomas and interferon and systemically, parenterally, or sional agent. fluorouracil are the most frequently topically, rather than excluinvestigated nonmelanoma skin cancers sively intralesionally; theraMedication and chemotherapeutics, respectively, in peutic outcome was not administration studies of intralesional chemotherapy. reported; excision was perMany authors used a 26formed before the use of or 30-gauge 3/8-in needle on Systemic toxicity can occur with intralesional chemotherapy; a tuberculin syringe to inject intralesional placement of these and proprietary or experithe medication. Of the 56 chemotherapeutic agents. Toxicity mental formulations of the references, 28 described the depends on the agent used, features of medication were used that method of medication inocthe regimen, and comorbidities of the are not currently or widely ulation; 3 methods were the patient. Baseline and intermittent available. Articles using elecmost commonly used. One laboratory monitoring is recommended troporation or needleless inmethod used tangential inas a precaution for all patients. oculator for drug delivery jection of 4 equal aliquots of Few studies have assessed the long-term were also excluded, because medication into the quadcure rates of intralesional chemotherapy, these methods of drug delivrants of the surface of the making it difficult to compare with ery are not widely used. In all, tumor and a fifth injection standard surgical modalities. 56 articles fulfilled the criteria into the base. A second and were used for data method deposited the medicollection. cation via multiple injections at the periphery, with The following data were extracted from each or without an injection into the base. The third article and included in our review: treatment medmethod injected at one or two sites of the tumor until ication, number of patients, drug concentration, the dermis blanched or a peau d’orange effect was dose per treatment, frequency of treatments, total seen. Multiple authors noted a loss of up to 30% to dosage, number of cancers with complete remission, 50% of the volume of the injection flowing from the length of follow-up, side effects, laboratory monisurface of the tumor, particularly when treating toring, and if pretreatment or posttreatment biopsies friable KA or SCC.2-4 were performed. Characteristics of the tumors were also collected, including type of cancer (KA, BCC, Methotrexate SCC), location, and size. Histologic subtype of BCC Eight references report the use of intralesional was recorded whenever possible. It was also reMTX to treat KA.2,4-10 There are no reports of its use corded when posttreatment cure rates were deteron SCC or BCC. Six articles reported the treatment of mined by clinical appearance or biopsy 36 tumors (Table I). Two sources reported adverse confirmation. Complete response (CR) rates were events without remarking on clinical outcome, so calculated using all tumors reported to be cured, were not included.7,9 In all, 26 (72%) of the tumors d

d

d

d

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NR 1.0-3.0/1.8 3.5 2 Average: 1.98

NR 12.5-25 25 5

NR NR 37.5 mg 5 mg Average: 12 mg

3 1-2/1.7 2 5 Average: 2.2

14 14 14 7

19.5 5-50/21.9 75 25 Average: 33.8

1/1 (100%) 9/9 (100%) 1/1 (100%) 1/1 (100%) Total: 33/36 (91.7%)

NR 1-35/15 48 1 Average: 19.5

were on the face, scalp, or ears; 5 (14%) on the hand; 4 (11%) on the leg; and one (3%) on the chest. Of the tumors, 24 (67%) were biopsy proven. Of the 36 tumors treated, a cure was defined clinically in 33 (91.7%). Posttreatment biopsy was done in two (5.5%) cases. Although not specified for all cases, clinical follow-up ranged from 1 to 91 months, with an average of 19.5 months. No recurrences were noted. Laboratory monitoring (Table V) throughout the therapeutic period was performed for one case and revealed normal findings.6 Two cases of pancytopenia after one dose of intralesional MTX were reported in two patients with end-stage renal disease on hemodialysis.7,9

KA, Keratoacanthoma; NR, not reported.

KA KA KA KA report series report report Case Case Case Case

1/1 9/9 1/1 1/1 Total: 36/36

12-38/22 1.875-87.5/36 15/18 (83%) 1-91/23 NR 12.5-62.5/33.3 6/6 (100%) 10-20/13 1-3/2 1-4/2.4 NR NR/40 mg 12.5 or 25 25 1.0-3.5/2.1 1.0-2.8/1.8 18/18 6/6 KA KA Case series Case series

Annest et al, 2007 Cuesta-Romero and de Grado-Pena,6 1998 Cohen et al,10 2005 Melton et al,4 1991 de Visscher et al,8 2002 Spieth et al,5 2000

References

2

Type of study

Table I. Intralesional methotrexate

Tumor type

No. of tumors/ patients

Tumor diameter/ mean, cm

Drug concentration, mg/mL

Dose/ mean

No. of treatments/ mean

Treatment frequency/ mean, d

Total dose/mean, mg

Cure rate

Length of follow-up/ mean, mo

VOLUME 63, NUMBER 4

5-Fluorouracil Nine articles reported the use of 5FU on 82 KAs.11-19 Three articles reported the use of 5FU in 23 BCCs.12,20,21 Table II summarizes the data from these 12 studies. In all cases 5FU was administered undiluted in a concentration of 50 mg/mL. At least 68 KAs were treated; 26 of the tumors were located on the arm or hand, 24 were on the head or neck, and 3 were on the leg. Pretreatment biopsies were performed on 13 tumors: 10 solitary KAs and a single representative lesion on 3 patients with multiple tumors. In all, 67 (98.5%) tumors were considered clinically cured. The one tumor that did not respond was reported by Odom and Goette.16 The KA was located on the earlobe and did not involute after 5 treatments; subsequent excision removed the tumor 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 24 months or more without recurrence.12 Laboratory testing (Table V) was done in 6 patients without any abnormal finding.13,16 Three articles reported the use of 5FU in 23 BCCs. One tumor was excluded because topical 5FU was used immediately before intralesional use for a BCC.12 This case was also reported twice: once in a larger series and once as a case report to describe the diagnosis of SCC in a persistent papule at the BCC treatment site.20 All of the tumors were located on the head and neck. Tumor size was not reported for most cases. All tumors were biopsy proven. Histologic subtype of the BCC, when reported, was infiltrative, superficial, or nodular.12,21 The BCCs were recurrent in 3 cases and previously treated singly or serially with surgery, 5FU ointment, or radiograph therapy.21 Of the BCCs, 23 (100%) were clinically cured with intralesional 5FU. Four of the sites had posttreatment biopsy results that confirmed a cure.12,21 Duration of follow-up was not noted. No recurrences were

692 Kirby and Miller

Table II. Intralesional fluorouracil

References

Kurtis and Rosen,12 1980 Avant and Huff,21 1976

Dose/ mean, mg

No. of treatments /mean

Type of study

No. of tumors/ patients

Tumor diameter /mean, cm

Drug concentration, mg/mL

BCC

Case series

2/2

1.7-2.9/NR

50

NR

BCC

Case series

21/3

NR

50

50-150/NR 4-8

Tumor type

5-6/5.5

Treatment frequency/ mean, d

Total tumoral dose/mean, mg

3

500-725/612.5

Cure rate

Length of follow-up /mean, mo

2/2 (100%)

NR

NR

21/21 (100%)

NR

3

177.5-585/354

Total: 23/23 (100%) 3/3 (100%)

NR

7

NR

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

9

3-14/NR

Total: 23/5 Kurtis and Rosen,12 1980 Goette and Odom,15 1980 (includes patients from Odom and Goette,16 1978) Klein et al,17 1962 Singal et al,11 1997 Leonard and Hanke,14 2006 Eubanks et al,19 1982 Parker and Hanke,13 1986 Morse et al,18 2003

KA

Case series

3/3

0.8-1.3/1.0

50

NR

KA

Case series

41/30

KA KA

NR

50

NR; range, NR/3 40-75

Case series 2/2 Case report Numerous/1

NR 0.1-2

50 50

5 10-15

7-34/20 3

0.5-2/1.25 7

3.5-170/86.75 30-45/NR

KA

Case report

1/1

4

50

NR

8

7-14/NR

NR

2/2 (100%) Numerous (100%) 1/1 (100%)

KA KA

Case report Case series

14/1 5/4

0.4-1.1 2.2-6.0

50 50

10-20/NR 5-9/NR 50-150/NR 2-5/3.8

7 7-28/NR

NR 100-600/360

14/14 (100%) 5/5 (100%)

6 18-45/30

KA

Case report

50

40-120/80

680 Average: 341

1/1 (100%) Total: 87/68 (98.5%)

5

1/1 3.3 Total: $ 93/57

6-12/8.3

8

7

NR NR

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

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24

reported. Laboratory monitoring was not done in any study.

BCC, Basal cell carcinoma; KA, keratoacanthoma; KCM, keratoacanthoma centrifugum marginatum; NR, not reported; SCCis, squamous cell carcinoma in situ. Bleomycin conversion rates: 1 mg = 1500 IU = 2 U(USP).60

8/8 (100%) Total: 12/12 (100%) 0.00175 2 7 .00025 0.0007 NR Case report BCC

8/1 Total: 12/5

48 3-24/NR 8/8 (100%) 1/1 (100%) 3/3 (100%) Average: 0.64 3.175 NR 21-42 NR 0.5 0.2 Total: 8/8 1/1 3/3 Case report Case series

Dyall-Smith,27 1998 Mishima and Matunaka,26 1972 Gyurova et al,25 2006

SCCis BCC

Average: 1.98 2.3 NR

Average: 0.3 Average: 1.75 NR 7 NR 4-20/NR

0.5-3/NR 6/6 (100%) 0.1-0.8/0.38 7-14/9.3 1-2/1.5 0.5 6/6 Case series KA

0.7-1.9

0.1-0.4/0.25

18 1/1 (100%) 0.4 7 2 0.5 1/1 Case report KA

2

0.2

48 1/1 (100%) 1.2 7 3 0.4 0.5 7 1/1 Case report KCM

References

de la Torre et al,23 1997 Andreassi et al,24 1999 Sayama and Tagami,22 1983

No. of tumors /patients Type of study Tumor type

Table III. Intralesional bleomycin

Tumor diameter /mean, cm

Drug concentration, mg/mL

Dose/ mean, mg

No. of treatments /mean

Treatment frequency /mean, d

Total dose/mean, mg

Cure rate

Length of follow-up /mean, mo

VOLUME 63, NUMBER 4

Bleomycin Intralesional bleomycin was reported in 3 studies for the treatment of KA,22-24 two studies for BCC,25,26 and one case report described the treatment of SCC in situ (SCCis).27 Of the 6 total studies (Table III), 5 administered the bleomycin diluted 1:1 with an anesthetic (lignocaine, lidocaine, or Marcaine) to minimize pain associated with the injections.22-25,27 Three studies reported 8 KAs treated with intralesional bleomycin.22-24 Six (75%) of the tumors were on the face, one (12%) on the arm, and one (12%) on the leg, which was characterized as a KA centrifugum marginatum. All 8 (100%) of the KAs were considered clinically cured and none had posttreatment biopsies. The tumors were followed up for 2 weeks to 4 years, with an average observation period of 9 months and there were no reported recurrences. Intralesional bleomycin has also been used to treat 11 BCCs on 4 patients in two case reports.25,26 Ten (91%) tumors were located on the face or ear and one (9%) tumor was on the back. Pretreatment biopsy was done on at least 9 (82%) of the BCCs. All 11 (100%) were considered clinically cured and none had a posttreatment biopsy. The patients were followed up for 3 to 48 months without a reported recurrence. Laboratory monitoring (Table V) was done in one patient treated for 8 tumors and no abnormal findings were reported.25 Interferon Interferon alfa-2, -2a, and -2b, and the combinations of these have been administered intralesionally to treat BCC, SCC, and KA. Intralesional interferon beta and gamma have been used to treat BCC.28-31 Table IV summarizes the characteristics of the studies using intralesional interferon. BCC and interferon alfa Interferon alfa-2a was used to treat BCC in 5 reports on 66 tumors.32-36 The tumors were located on the head and neck in 63 (95%) of the patients; the 3 (5%) remaining tumors were on the trunk. All tumors had a pretreatment biopsy. Nine (14%) of the tumors had an infiltrative or morpheaform growth pattern, whereas the remaining tumors had a nodular, ulcerative, or superficial growth pattern. The dose was determined by the size of the tumor in 55 (83%) of the tumors. All treatment sites had a posttreatment assessment; biopsies were performed on 51 (77%) sites and a superficial

References KA and interferon Wickramasinghe et al,51 1989 Grob et al,55 1993 Oh et al,56 2004

Tumor Interferon type type KA KA KA

Interferon alfa-2 Interferon alfa-2a Interferon alfa-2b

Type of study

Tumor diameter/ mean

No. of tumors/ patients

Open-label trial

1/1

NR

Open-label trial

6/6

2-3.5 cm

Case series

4/4

1.6-2.1/1.8 cm

3 NR 3

Total: 11/11 SCC and interferon Wickramasinghe SCC Interferon et al,51 1989 alfa-2 SCC, Interferon Edwards et al,53 1992 SCCis alfa-2b SCC, Interferon Kim et al,47 2004 SCCis alfa-2b

Open-label trial Open-label trial Case series

3/3 34/34 3/3

alfa BCC BCC BCC BCC

Interferon alfa Interferon alfa Interferon alfa-2a Interferon alfa-2a

Open-label trial

11/11

Open-label trial

6/6

Open-label trial

Total dose/ mean, mU

Treatment No. of treatments/ frequency/ mean, d mean 9

TIW

8.1

1/1 (100%)

3

2-6/5

9-20/12

TIW

24-117/57

6/6 (100%)

6-36/18

3

4-6/5

7

12-18/15

4/4 (100%)

19-27/24.5

Average: 3.8

Average: 9

Average: 37.3

3

0.9

9

TIW

8.1

0.5-2 cm

10

1.5

9

TIW

13.5

NR

NR

2-2.5/2.2

9-12/10

TIW

18-30/22

Average: 1.5

Average: 9

Average: SCC = 13; SCCis = 15

3/3 (100%)

3 23-42/30

Total: 39/40 (98%)

9

TIW

8.1

0.7-1.4 cm

10

1.5

9

TIW

13.5

11/11

0.5-2 cm

NR

1.5

9

TIW

13.5

Open-label trial

20/13

Area: 0.3-7 cm2

NR

\2 cm2: 1.5; [2 cm2: 3

9

TIW

13.5 or 27

Area: 0.2-6 cm2

NR

\0.6 cm2: 3; 0.6-2 12 cm2: 4.5

TIW

36 or 54

3-35/11 cm2

NR

TIW

24-156/74.6

Area: 0.5-8.75 cm2

NR

TIW

15 or 30

NR

\2 cm2: 1.5; 2-12 18-33/23 cm2: 4.5; [12 cm2: 6 \2 cm2: 1.5; [2 10 cm2: 3 1-2/1.5 9

TIW

9-18/13.5

3/3 (100%)

22-23/22.7

TIW

13.5

2/6 (33%)

2

3/3 (100%)

20, 1 Recurrence

Grob et al,34 1988

BCC

Interferon alfa-2a

Open-label trial

8/7

Alpsoy et al,35 1996 Kim et al,47 2004 Mozzanica et al,40 1990 McDonald and Georgouras,48 1992 Tucker et al,49 2006

BCC

Interferon alfa-2a Interferon alfa-2b Interferon alfa-2b Interferon alfa-2b

Open-label trial, randomized Case series

15/15 3/2

NR

Open-label trial

6/6

1.5-3.0 cm

3

1.5

Case report

3/1

Area: 1.5-5.4 cm2

3

\2 cm2: 1.5; 2-12 8-18/14 cm2: 4.5

TIW

24-54/43

Interferon alfa-2b

Case series

98/98

NR

5

1.5*

NR

13.5y

9

9

6/6 (100%) 8/11 (73%)

3 2 13-18/NR

11/20 (55%), 8/11 84, 1 Recurrence CR were \2 cm2 11/13 (85%), 4/4 12 CR were \0.6 cm2 8/8 (100%) 3-8/5

10/15 (67%)

67/69 (97%)

2

84

OCTOBER 2010

13/13

1/11 (9%)

J AM ACAD DERMATOL

Open-label trial

BCC

33/34 (97%)

3

0.9

Interferon alfa-2a

BCC

3/3 (100%)

3

BCC

BCC

Total: 11/11 (100%)

NR

Dogan et al,32 1995

BCC

Length of follow-up/ mean, mo

Cure rate

0.9

NR

Total: 40/40

BCC and interferon Wickramasinghe et al,51 1989 Greenway et al,52 1986 LeGrice et al,33 1995 Bostanci et al,36 2005

Dose/ mean, mU

Drug concentration, mU/mL

694 Kirby and Miller

Table IV. Intralesional interferon

\2 cm2: 1.5; [2 cm2: 3 1.5

12-24/NR

TIW

NR

9

TIW

13.5

6/10 (60%)

3-21/14

3

1.5

9

TIW

13.5

19/25 (76%)

12-38/24

\3 cm

10

1.5

9

TIW

13.5

14/27 (52%)

2-12/NR

4/4

NR

5

1.5

6

TIW

9

4/4 (100%)

1

3/1

NR

NR

1.5

9

TIW

13.5

0/3 (0%)

NR

Interferon alfa-2b Interferon alfa-2b

Open-label trial

140/140

Open-label trial

BCC

Interferon alfa-2b

BCC

Interferon alfa-2b Interferon alfa-2b Interferon alfa-2b Interferon alfa-2b Interferon alfa-2b Interferon alfa-2b

BCC

BCC BCC BCC BCCz BCC

0.3-5 cm

NR

10/10

0.7-1.9 cm

NR

Open-label trial

25/25

0.5-2 cm

Open-label trial

27/27

Open-label trial Case report

10/10

0.5-2 cm

NR

1.5

9

TIW

13.5

6/10 (60%)

12-26/17

Open-label trial

15/15

0.7-2.5 cm

10

1.5

9

TIW

13.5

4/15 (27%)

2

Interferon: 120; Randomized placebo: 42 placebo controlled trial

0.5-1.5, 0.5-2 cm for superficial

10

1.5 or placebo

9

TIW

13.5

NR

\2 cm2: 1.5; [2 cm2: 3

10

TIW

15 or 30

0.5, 1.0, 3.0/1.3

3, 6, 9/6.6

7, 3, TIW/2.2 3-18/7.7

1

9

TIW

Interferon alfa-2b

Open-label trial, randomized

15/15

Area: 0.6-8.2 cm2

Interferon beta

Open-label trial

69/69

0.5-2 cm

9.6 or 19.2

Kowalzick et al,29 2002

Interferon beta

Open-label trial

133/133

0.5-2 cm

NR

Total: 202/202 BCC and interferon gamma Edwards et al,31 BCC Interferon 1990 gamma Tank et al,30 1989

BCC

Interferon gamma

12-54/36

Open-label trial

Alpsoy et al,35 BCC 1996 BCC and interferon beta Kowalzick BCC et al,28 1994 BCC

94/140 (67%)

Open-label, randomized trial Open-label trial

29/29

7/7 Total: 36/36

9 Average: 9.9

Nodular: 0.5-2 cm; superficial: # 3 cm 0.8-2.2 cm

12, 7 Recurrences Interferon: 103/120 (86%); placebo: 12/42 (29%) 10/15 (67%) 2

35/69 (50%), range, 14%86% 89/133 (67%)

3, 4 Recurrences

Median = 24, 1 recurrence

Total: 124/202 (61%)

2 10

0.02 0.1

9 9

TIW TIW

0.18 9

1/14 (7%) 7/14 (50%)

3

2

0.02

8

3

0.16

0/7 (0%)

2

Average: 0.025

Average: 0.23

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BCC

VOLUME 63, NUMBER 4

Chimenti et al,45 1995 ThestrupPedersen et al,46 1990 Pizarro and Fonseca,38 1994 Boneschi et al,39 1991 Buechner,41 1991 Kopera et al,42 1996 Healsmith et al,43 1991 Stenquist et al,44 1992 Cornell et al,50 1990

8/35 (22%)

Kirby and Miller 695

BCC, Basal cell carcinoma; CR, complete response; KA, keratoacanthoma; NR, not reported; SCC, squamous cell carcinoma; SCCis, squamous cell 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. y Large tumors received higher cumulative dose because of serial treatments (see above). z All BCC were recurrent tumors or primary morpheaform type.

696 Kirby and Miller

Table V. Medication mechanisms, contraindications, monitoring, and cost Medication: Mechanism of action

Methotrexate: Antagonist of folate metabolism, inhibits DNA synthesis

Fluorouracil: Antimetabolite and structural analog of uracil, disrupts DNA and RNA synthesis Bleomycin: Cytotoxic by damaging DNA

Interferon (alfa, beta, or gamma): Antiproliferative and immunoregulatory

Contraindication/cautious use

Laboratory monitoring

Side effects

Cost

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 Liver disease; pregnancy or breastfeeding; allergy to medication; maximum daily recommended dose: 800 mg Pregnancy, breast-feeding

$25/250 mg (10 mL) Baseline: CBC diff, LFT, BUN, Cr Local: pain, erythema, crusting, Before subsequent treatments: ulceration, necrosis CBC diff (LFT not needed because Systemic: cytopenias, pulmonary liver disease is associated with fibrosis, gastrointestinal upset, chronic use) diarrhea, stomatitis, hepatotoxicity, nephrotoxicity, teratogenicity

Renal insufficiency or hemodialysis; liver disease; pregnancy, breastfeeding; autoimmune disease; hematopoietic disease; avoid concomitant use of NSAIDs*

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

Baseline: CBC diff Weekly: CBC diff

Baseline: CBC diff Weekly: CBC diff

Local: pain, erythema, crusting, ulceration, necrosis Systemic: cytopenias, gastrointestinal upset Local: pain, erythema, crusting, ulceration, necrosis Systemic: pulmonary toxicity, Raynaud phenomenon, skin sclerosis Local: pain, erythema, crusting, ulceration, necrosis Systemic (dose-dependent): fever, malaise, myalgias, headache, emotional lability, alopecia, nausea, cytopenias, hepatotoxicity, nephrotoxicity

$26/250 mg (50 mL)

$350/15-mg vial

$395/22.8-mU vial interferon alfa-2b $2175/4-mU vial interferon beta

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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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98% (54/56) 92% (33/36)

22% (8/36) 50% (7/14)31 90% (28/31) 89% (10/11) 91% (10/11)

68% (45/66) 100% (8/8)34

BCC Subgroups with highest cure rates* SCC SCCis KA

BCC, Basal cell carcinoma; KA, keratoacanthoma; SCC, squamous cell carcinoma; SCCis, squamous cell carcinoma in situ. *Subgroups of BCC, often in small numbers, had substantially better cure rates than overall group. This is listed separately with corresponding reference so method of treatment can be considered.

92%59

92%57 97%57

98%-100%59

90%57

100% (1/1) 100% (8/8)

Excision

99%57

Bleomycin Interferon beta

68% (128/202) 84% (12/14)28

Interferon alfa-2a Tumor

76% (363/479) 98% (96/98)49

Interferon gamma Interferon alfa-2b

Table VI. Comparison of cure rate for surgical modalities and intralesional therapy

Methotrexate

Fluorouracil

96% (23/24)

100% (11/11)

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scraping was done on 15 (23%) sites. CR occurred in 45 (68%) of the tumors. The CR for all BCCs larger than 2 cm2 was 73% (16/22) whereas the CR improved slightly to 76% (16/21) when these larger tumors were treated with a higher dose based on their size.32-34,36 The duration of follow-up ranged from 3 months to 7 years, with an average of 18 months. There was one (1.5%) recurrence.36 Some patients took acetaminophen at the time of treatment.35 Patients were asked to avoid nonsteroidal anti-inflammatory drugs in all studies. Laboratory testing (Table V) was done at baseline and during the treatment course for all of the patients. Elevated liver function tests were reported in one patient.35 None of the patients stopped therapy because of side effects or changes in laboratory results. Fifteen articles discuss the use of interferon alfa2b for the treatment of 542 BCCs.35,37-50 Of these, 65 were treated in a study using a sustained-release formulation of interferon alfa-2b and will be considered separately.37 The remaining 477 tumors were located on the head and neck in 298 (62%) of the cases, on the trunk in 140 (30%), and on the extremities in 38 (8%). The location of one treated tumor was not reported. Seven of the studies excluded tumors larger than 2 or 3 cm in diameter and account for 302 (65%) of the tumors treated with interferon alfa-2b. Overall, pretreatment biopsy was performed on 415 (87%) of the tumors. The histologic type of BCC included 161 (34%) superficial tumors, 256 (54%) nodular tumors, 29 (6%) ulcerative type, 22 (4%) infiltrative or morpheaform type, and 9 (2%) recurrent tumors. Four studies determined 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 a median time of at least 1 year and reported 6 (1.6%) recurrences. Laboratory monitoring (Table V) was reported in 10 of the 15 articles. Reversible cytopenias occurred in 30 patients and elevations (\3 times) of liver function tests occurred in 9 patients. No patient discontinued treatment because of laboratory changes. Individual studies treated BCC with a sustainedrelease formulation of interferon alfa-2b,37 the combination of interferon alfa-2a and -2b,35 or an older formulation of interferon alfa-250,51 (not specifically alfa-2a or -2b). First, sustained-release interferon alfa-2b was used on 65 patients; 63 patients completed the study and two dropped out because of systemic side effects. One group of 33 tumors was treated with one dose of 10 mU in a volume of 0.2 mL; 17 (52%) were cured with histologic confirmation. 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 basal cell carcinoma KA

Tumors cured/treated Diameter, cm Dose Treatments Frequency Total dose

BCC

MTX

5FU

Bleomycin*

Interferon alfa-2a

33/36 (92%) 1.98 12 mg 2.1 1-2 wk 33.8 mg

54/55 (98%) 2.1 40 mg 7.7 1 wk 341 mg

8/8 (100%) 1.27 0.24 mg 1.6 1 wk 0.36 mg

45/66 (68%) na 2.6 mU 11.5 TIW 34 mU

Interferon alfa-2b

363/489 (76%) na 1.5 mU 9 TIW 13.5 mU

Interferon beta

128/202 (63%) na 1.1 mU 9 TIW 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.

with 3 weekly doses of 10 mU; 24 (80%) were cured with histologic confirmation.37 Alternating doses of interferon alfa-2a and -2b were used 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 studies.51,52 BCCs were given 0.9 mU (11 tumors) or 1.5 mU (8 tumors) 3 times weekly for 3 weeks (9 total doses). None of the tumors treated with the 0.9-mU dose had a cure. All 8 (100%) of the tumors treated with the 1.5-mU dose had a histologic CR. If all tumors treated with interferon alfa-2 and -2b are considered together, the overall CR decreases from 76% to 74.5%. SCC and interferon alfa. In all, 31 invasive SCCs and 9 SCCis treated with interferon alfa-2 or -2b were reported in 3 articles.47,51,53 The location of the tumors, when specified, was on the legs, hand/digit, ear, or other site with surrounding sun damage. All cases had a pretreatment biopsy. A CR was achieved in 37 (92.5%) cases. The cure rate for invasive SCC and SCCis was 90% (28/31) and 89% (8/9), respectively. Posttreatment biopsies were done on all but one (3%) SCC and all but two (22%) SCCis. Two patients treated for SCCis developed a second malignancy; one patient developed a dermatofibroma sarcoma protuberans 1 year later at a different site and another patient was given a diagnosis of chronic lymphocytic leukemia 6 months later.54 Laboratory testing (Table V) was done in 30 (75%) of the patients. Seven had elevated liver function test results and 3 had changes in their complete blood cell count; none discontinued therapy and all changes normalized 5 weeks after treatment.53 Side effects were not noted in those receiving the lowest treatment dose of 0.9 mU51 but occurred in 65% of those receiving 1.5 mU per treatment.53 KA and interferon alfa. Three articles reported the 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 the hand. Pretreatment biopsy was done on 8 tumors. The tumors were cured in 10 (91%) cases and confirmed by posttreatment biopsies in 4 (36%) cases. One tumor was excised after 3 weeks because of lack of improvement. The individual CR for interferon alfa-2, -2a, and -2b were 100% (1/1), 83% (5/6), and 100% (4/4), respectively. Follow-up ranged from 6 to 36 months with an average of 20 months and no recurrences were reported. Laboratory testing (Table V) was performed in 10 (91%) patients and only one patient developed neutropenia, but did not discontinue therapy.55 BCC and interferon beta. Intralesional interferon beta has been used to treat 202 BCCs.28,29 The sites of the tumors were not specified. Pretreatment biopsy was done in all patients. Morpheaform types of BCC were excluded from the study. Nodular, superficial, and ulcerative subtypes of BCC were included; the number of each was not specified in either source. In all, 124 (61%) tumors had a CR and all 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 Laboratory monitoring (Table V) was done for all patients and none had ‘‘significant’’ laboratory changes. The outcome was judged to be good to excellent and without scarring aside from prior biopsy sites. BCC and interferon gamma. Interferon gamma was used in two studies to treat 36 tumors in as many patients.30,31 One study did not report sites of the tumors; in the second study, 6 were on the head or neck and one was on the leg. Pretreatment biopsies were done on all 36 (100%) tumors. In all, 21 (58%) were nodular and 15 (42%) were superficial; morpheaform BCC were excluded from both studies. Overall, CR occurred in 8 (22%) cases and 7 of these were treated with the highest dose regimen.31 The

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treatment site was excised 2 to 3 months after the end of treatment, so all CR were confirmed by pathology. Laboratory monitoring (Table V) was done in all patients at baseline and during treatment and no abnormal findings were reported.

DISCUSSION Surgery 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. In select circumstances, for example when excisional modalities have repeatedly failed or are not possible, the treatment of tumors with intralesional chemotherapy may be a reasonable option (Table VI). The lack of well-designed trials or guidelines for the use of intralesional chemotherapy leaves the clinician with little evidence to guide decisions on this modality. By summarizing the literature, this comprehensive review may help clinicians use intralesional chemotherapy to treat SCC, KA, and BCC with greater confidence and safety. Clinicians may consider several variables when selecting the ideal intralesional chemotherapy agent. The mechanisms of action, contraindications, sideeffect profiles, recommended laboratory monitoring, and cost are summarized in Table V. Although the potential systemic side effects can be serious, most side effects from the drugs occur at the site of injection and are comparable among all the agents. Choice of intralesional agent may depend on type of tumor. KAs have been treated with MTX, 5FU, interferon alfa-2a, and bleomycin; however, MTX and 5FU have been used on more tumors than the other agents. The CR for MTX and 5FU were 92% and 98%, respectively. Both therapies were administered weekly in most cases and were well tolerated. In our opinion, both MTX and 5FU are reasonable first choices for intralesional chemotherapy of KA. SCC, both in situ and invasive, has been treated with interferon alfa-2a and bleomycin; however, only 43 tumors have been treated. Bleomycin was used in a single case, so the true use of this agent is unknown. We believe further studies should be undertaken before it can be recommended. Interferon alfa-2a demonstrated a CR of 90% and 89% for SCC and SCCis, respectively. This is not very dissimilar to the 92% CR rate of conventional excision.57 Flu-like symptoms occurred in many patients given intralesional injections and patients should be counseled regarding this effect. BCC represents the majority of tumors treated with any type of intralesional chemotherapy. Interferon alfa-2a, alfa-2b, beta, and gamma; 5FU; and bleomycin have been reported. The CR of the interferons (alfa,

beta, or gamma) are all inferior to the CR of conventional excision and Mohs micrographic surgery (Table VI). Subgroups of tumors treated with interferon demonstrated better efficacy than the overall group. Interferons alfa-2a, alfa-2b, beta, and gamma have shown CR as high as 100%, 98%, 84%, and 50%, respectively. Because these were subgroups, a smaller number of BCC were treated: 8 with interferon alfa-2a, 98 with interferon alfa-2b, 14 with interferon beta, and 14 with interferon gamma. Bleomycin and 5FU have been used on fewer BCC than interferon. Eleven tumors were treated with bleomycin and 24 with 5FU, resulting in a CR of 100% and 96%, respectively. These rates of clearance are better than those reported with conventional excision and not very dissimilar from those reported after Mohs micrographic surgery.57 Although the sample size is small with these agents, the CR is impressive. Further study is worthwhile and the use of bleomycin and 5FU could be considered in patients not amenable to surgery. High-risk histologic subtypes of BCC such as morpheaform, infiltrative, or recurrent tumors were often excluded from the studies. Six reports did include these types of BCC; interferon alfa-2a was used in 3 reports and interferon alfa-2b was used in 4. One study used interferon alfa-2a, -2b, or both.34-36,38,44,47 Dose and frequency of interferon was similar to the majority of BCC treated with these agents. A total of 37 tumors were treated: 7 with interferon alfa-2a, 28 with interferon alfa-2b, and two with the combination of interferon alfa-2a and -2b; the CR was 100%, 54%, and 50%, respectively. Long-term follow-up was not reported. In contrast, Mohs micrographic surgery can deliver 5year relapse-free survival in 94% of cases for these same types of BCC.58 We recommend interferon therapy for high-risk subtypes of BCC only when Mohs micrographic surgery is not an option. Multiple methods of depositing the drug have been described, and there have been no studies to assess the efficacy of the method of drug delivery. In general, injections are placed strategically to infiltrate the periphery and base of the tumor.21,37,53 Blanching of the tumor and a peau d’orange change serve as clinical markers for effective infiltration. Large or multiple tumors may require a volume of medication that approaches the maximum recommended dose. In these instances, segmental treatment (of a 2-cm2 portion at a time) using the drug regimens suggested above for smaller tumors is an option. Tumor dose and frequency of injection vary widely. Some studies used size-based doses; multiple studies used 2 cm2 as the threshold to determine if a tumor smaller or larger would receive a lower or higher 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 protocol until the tumor became crusted, friable, and/or ulcerated then allowed the area to heal before resuming injections.13,21 By contrast, several authors continued regular treatment even if the lesion was necrotic.3,11,14,16,18,19 In general, frequency and number of injections was determined by tumor destruction, reduction in size, or both. Local side effects are similar with each of the 4 agents examined. Injections of 5FU or bleomycin are reported to be more painful, so it is common to pretreat with intralesional anesthetic.12-14,20-22,24,27 In contrast, local anesthesia is not used when administering MTX or interferon. There have been no studies to determine the potential for dilution or alteration of effect when anesthetic is used. Intralesional administration caused some degree of pain, erythema, crusting, ulceration, necrosis, or a combination of these. These site-limited reactions were often well tolerated and very few patients discontinued therapy for this reason. Potential systemic adverse effects of each medication are listed in Table V. Systemic side effects with all of these medications are more common when they are administered parenterally, but intralesional administration does not eliminate the risk. Monitoring blood work was performed in the minority of studies, but done most consistently in those administering interferon. Of the 127 tumors treated with MTX, 5FU, or bleomycin, only 8 patients had monitoring blood work performed starting at baseline through the end of treatment. None of these patients had abnormal findings requiring discontinuation. Two patients on hemodialysis treated with MTX for KA developed pancytopenia and discontinued therapy. Laboratory monitoring was not planned in either patient but was done after they developed hemorrhagic skin lesions. In comparison, 923 tumors in 28 studies were treated with interferon alfa, beta, or gamma and 22 of the studies required laboratory monitoring. Reversible laboratory changes, most commonly cytopenias, were reported but none necessitated discontinuation of the medication. The absence of evidence demonstrating risk does not equal the absence of risk so it is recommended that baseline and monitoring blood work be performed. Cure rates were most often clinically determined and posttreatment biopsies were not done in many studies. Cure rates for each drug are summarized in Table VI. Clinical CR would likely overestimate the true CR because occult tumor would not be identified. When performed, posttreatment biopsies were performed either soon or delayed from the end of treatment. A delay in performance of a

posttreatment biopsy may have allowed for further resolution of the tumor or vice versa allowed for resolution of an inflammatory infiltrate that could obscure residual tumor. Many patients had followup periods of less than a year; however, some were followed up for longer. A short follow-up period would contribute to inflation of the efficacy of intralesional chemotherapy. The cosmetic outcomes were similar with all types of intralesional chemotherapy. None of the studies used a formal method to grade outcomes by investigators or patients. Outcomes were often briefly reported in the ‘‘Discussion’’ section if they were described at all. Trends for cosmetic outcomes by type of medication or type of tumor could not be determined because of the lack of detail in the primary sources. Overall, authors rated cosmetic outcomes as good or excellent and with minimal to no scarring. Small scars from pretreatment biopsies were noticed in some patients. Some sites were slightly depressed after treatment and may have been a result of either the effects of the medication or tissue destruction by the tumor.34 Pigmentary changes, such as hypopigmentation or hyperpigmentation, were not uncommon.3,4,12,21,25,51,55,56 Authors did not report if these changes improved at subsequent follow-up visits. Patients with large KA had some destruction of normal tissues with subsequent clefting or notching and required surgery for cosmetic reconstruction.14,55 Two patients developed milia at the treatment site after MTX for a KA.34 No additional reports of milia at a treatment site were found. In summary, it is reasonable to counsel patients of the risk of scarring that may occur from pretreatment and posttreatment biopsies and from the intralesional therapy. For the reported cases, scars were slight to absent and when present were the same size or slightly smaller than the tumor. Postinflammatory erythema or dyspigmentation would be present initially but improve or resolve with time. Other drug-specific side effects such as serpentine hyperpigmentation associated with intravenous use of 5FU or flagellate hyperpigmentation with bleomycin has not been reported with the intralesional treatment of NMSC. Limitations of this review include those of the primary sources reviewed: the primary sources were often case reports or small case series so a small number of patients were treated; selection bias may have favored patients thought to be responders or, conversely, patients with advanced disease; investigators were not blinded; and posttreatment biopsies were not consistently performed so the reported CR may not be reflective of the true effect. In an effort to include as many cases as possible in this review,

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some patients with multiple tumors were counted as only one case because sufficient detail of each tumor was not included. This would underestimate the true effect of treatment when all lesions are cured. Reports of failures are less likely to be reported and published in the literature and therefore would inflate the CR of these agents. Follow-up for many of these studies was limited to 12 to 18 months; rarely was there observation for 5 years, which is an accepted threshold for the efficacy of a cancer treatment. One study reported follow-up after 15 years 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 of BCC on the nose and face (other than the nose). Based on the data collected, we conclude that intralesional chemotherapy can be an effective and well-tolerated treatment modality for NMSC (Table V). Care must be taken to chose tumors that are amenable, consider surgical modalities, and educate patients as to expectations of the course of treatment including local and systemic side effects, laboratory monitoring, need for posttreatment biopsies, and clinical follow-up. Some combinations of type of tumor and chemotherapy agent are not well supported (eg, SCC, SCCis, bleomycin) and more studies are needed before these can be recommended. Our final treatment recommendations include performing pretreatment and posttreatment biopsies; performing pertinent laboratory monitoring at baseline, during treatment, and after treatment; using an alternate treatment modality if the tumor grows or persists unchanged after 2 to 3 weeks of treatment; and clinical observation for recurrence. Table VII summarizes the characteristics of the therapeutic regimens for KA and BCC, the tumors with the most evidence to support the use of intralesional chemotherapy, and provides a possible starting point for treatment. REFERENCES 1. Miller SJ, Anderson J, Berg D, Bichakjian CK, Bowen G, Cheney RT, et al. NCCN clinical practice guidelines in oncology. Basal cell and squamous cell skin cancers. Available from: http://www. nccn.org/professionals/physician_gls. Accessed March 25, 2009. 2. Annest NM, VanBeek MJ, Arpey CJ, Whitaker DC. Intralesional methotrexate treatment for keratoacanthoma tumors: a retrospective study and review of the literature. J Am Acad Dermatol 2007;56:989-93. 3. Goette DK. Keratoacanthoma and its treatment. J Assoc Milit Dermatol 1984;10:3-10. 4. Melton JL, Nelson BR, Stough DB, Brown MD, Swanson NA, Johnson TM. Treatment of keratoacanthomas with intralesional methotrexate. J Am Acad Dermatol 1991;25:1017-23. 5. Spieth K, Gille J, Kaufmann R. Intralesional methotrexate as effective treatment in solitary giant keratoacanthoma of the lower lip. Dermatology 2000;200:317-9.

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