Fifty-Five Basal Cell Carcinomas Treated With

All patients applied 24 doses of imiquimod (Aldara, Fifty-five Basal Cell Carcinomas 3M Pharmaceuticals, St Paul, Minn) to the BCC lesion Treated With Topical Imiquimod: at night without occlusion. A 4-mm punch biopsy speci- Outcome at 5-Year Follow-up men was taken during the first 3 weeks of therapy to study the mechanism of action of imiquimod in BCC,2 and a final biopsy specimen was obtained 6 weeks after treat- oninvasive immunobiologic therapy with topi- ment to assess clearance of BCC. Patients whose BCCs cal imiquimod, 5%, cream is an emerging thera- had cleared after treatment were visited regularly for 5 N peutic option for basal cell carcinoma (BCC). years. The main outcome measures of the study were the Despite the documented short-term efficacy of imi- intent-to-treat long-term clearance rate and the recur- quimod for superficial BCC, few data exist on the long- rence rate of the imiquimod-treated BCCs. We used the term course of imiquimod-treated BCCs. In an effort to t test, ␹2 test, Fisher exact test, and multivariate analy- evaluate the long-term outcome of patients treated with ses in our statistical analysis (SPSS, version 11.5; SPSS imiquimod for BCC, we conducted a 5-year follow-up, Inc, Chicago, Ill). prospective, open-label study. Results. Fifty patients with a total of 4 superficial, 8 nodu- Methods. The sample size was 55 BCCs, and the cases were lar, and 43 infiltrative BCCs (n=55) were enrolled in 2001. assigned to 2 groups consecutively: 35 BCCs were treated The clinical and tumor characteristics are summarized 3 times weekly for 8 weeks, and 20 BCCs were treated 5 in the Table, and subject disposition during the study times weekly for 5 weeks. Inclusion criteria were age 18 is shown in Figure 1. years or older; primary BCC larger than 8 mm; and a su- Forty-two treated BCCs (76%) showed no clinical sign perficial, nodular, or infiltrative histologic pattern.1 Ex- of tumor or histologic tumor signs in the 6-week post- clusion criteria were pregnancy; immunosuppression; and treatment biopsy specimen; all of these patients were ob- genetic predisposition to BCC and other histologic sub- served periodically for a mean of 53 months (range, 10-61 types of BCC. Diagnosis was verified on histologic find- months). During this period, 1 patient died; 4 patients ings in 1 biopsy specimen prior to treatment. were lost to follow-up with no sign of recurrence at their

Table. Patient Characteristics, Pathologic Data, and Long-term Efficacy of Topical Imiquimod Treatment 62 Patients Screened in 55 BCC Lesions Treated With Topical Imiquimod* 12 Patients Ineligible

Imiquimod Dosing Regimen 50 Patients Enrolled 55 BCCs 4 Superficial BCCs 8 Weeks, 5 Weeks, 8 Nodular BCCs Characteristic 3 d/wk 5 d/wk Total 43 Infiltrative BCCs Total patients 32 (64) 18 (36) 50 (100) Imiquimod Dosing Regimen: Men 17 (53) 13 (72) 30 (60) 3 d/wk for 8 wk 5 d/wk for 5 wk Women 15 (47) 5 (28) 20 (40) BCCs = 35 BCCs = 20 Age, mean (SD), y 75.2 (7.6) 68.2 (14.6) 72.7 (11.0) 2 Superficial BCCs 2 Superficial BCCs 6 Nodular BCCs 2 Nodular BCCs Skin type 27 Infiltrative BCCs 16 Infiltrative BCCs II 11 (34) 7 (39) 18 (36) III 20 (63) 9 (50) 29 (58) 13 BCCs Failed to Clear IV 1 (3) 2 (11) 3 (6) 1 Nodular BCC BCC characteristic 35 (63) 20 (36) 55 (100) 12 Infiltrative BCCs Area, mean (SD), 121.8 (141.2) 113.9 (144.2) 118.9 (141.1) mm2 Posttreatment Follow-up 42 BCCs (76%) Erosion 16 (46) 12 (60) 28 (51) 4 Superficial BCCs Head 22 (62) 13 (65) 35 (64) 7 Nodular BCCs Trunk 11 (31) 2 (10) 13 (24) 31 Infiltrative BCCs Extremities 2 (5) 5 (25) 7 (12) Superficial 2 (6) 2 (10) 4 (7) 1 Recurrence After 10 mo 1 Infiltrative BCC Nodular 6 (17) 2 (10) 8 (15) Infiltrative 27 (77) 16 (80) 43 (78) 1 Patient Died After 25 mo BCC initial clearance 28 (80) 14 (70) 42 (76) 1 Infiltrative BCC Lost to follow-up 5 (17) 0 5 (12) or dead 4 Patients Were Lost to Follow-up After 30 mo Recurrence 0 1 (7) 1 (2) 1 Nodular BCC ITT long-term BCC 23 (65) 13 (65) 36 (65) 3 Infiltrative BCCs efficacy Superficial 2 (100) 2 (100) 4 (100) 36 BCCs Stayed Clear After 58 mo (65%) 4 Superficial BCCs (100%) Nodular 4 (66) 2 (100) 6 (75) 6 Nodular BCCs (75%) Infiltrative 17 (62) 9 (56) 26 (60) 26 Infiltrative BCCs (60%)

Abbreviations: BCC, basal cell carcinoma; ITT, intent-to-treat data set. *Unless otherwise indicated, data are reported as number (percentage) of Figure 1. Subject disposition during the study. BCC indicates basal cell patients or BCC lesions, whichever is appropriate. carcinoma.

(REPRINTED) ARCH DERMATOL/ VOL 143, FEB 2007 WWW.ARCHDERMATOL.COM 266

©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 last visit; and a 76-year-old woman developed a recur- rent infiltrative BCC after 10 months of follow-up. Late A relapses did not occur, and the 5-year recurrence rate was only 2% (1 of 37). None of the remaining 36 BCCs re- curred after a mean of 58 months of follow-up (range, 49-61 months). The cosmetic results were excellent in 33% of cases (n=24), but a permanent hypopigmented macule was ob- served in 67% of cases (n=12) (Figure 2). For the intent- to-treat data set, the long-term clearance rate for imiquimod was 65% for all BCCs (n=36), 100% for superficial BCCs (n=4), 75% for nodular BCCs (n=6), 60% for infiltrative BCCs (n=26), and 65% for both dosing regimens (n=23 and n=13). Multivariate analysis demonstrated that

only baseline BCC size had a significant association with B long-term clearance (P=.02) (odds ratio, 0.99; 95% con- fidence interval, 0.98-0.10): the smaller the tumor, the higher the chance to be cured with imiquimod.

Comment. To our knowledge, this is the first follow-up study examining topical imiquimod for the treatment of BCCs. Our long-term clearance rates of superficial and nodular BCCs are similar to the short-term rates found in randomized controlled trials, which range from 69% to 100% for superficial BCC3-8 and 42% to 76% for nodular BCC.8,9 Moreover, 60% of infiltrative BCCs in the pres- ent study did not recur by the end of the study. However, the comparison of our results with those of previously reported studies is complicated owing to dif- C ferences in patient and tumor selection, dosing regimens, number of biopsies performed, and follow-up times. Our results may be biased by the biopsy specimens taken during treatment, which could have removed tumor mass, increased imiquimod absorption, and/or induced a host immunologic reaction resulting in tumor regression. Nonetheless, our cases were treated with 24 doses of imiquimod on 2 dosing schedules. Imiquimod is ap- proved for 5-times-a-week dosing for 6 weeks (30 doses) for superficial BCC. Surprisingly, only 1 recurrence (2%) was found. Imiquimod treatment provided long-term clinical benefit in 36 (86%) of the 42 BCCs initially cleared. An ongoing 5-year study is currently being con- Figure 2. A 75-year-old woman with an infiltrative basal cell carcinoma (BCC) lesion on her right cheek. A, Prior to treatment with imiquimod 3 ducted in Europe to monitor possible recurrences of su- times per week for 8 weeks. B, At the end of the treatment period, showing perficial BCC following successful treatment with imi- marked erosion and crusting. C, After 5 years, showing hypopigmentation quimod.10 This study has enrolled patients with a total and clinical resolution of her BCC lesion. of 162 BCCs, and the interim 2-year results have shown 14 recurrences (recurrence rate of 8%), but this does not as paid speakers for 3M Pharmaceuticals. Dr Alomar has include a histologic assessment after therapy, as we did. also served as investigator and consultant to 3M Phar- In conclusion, our data suggest that imiquimod treat- maceuticals. ment is effective in most cases of noninfiltrative BCCs, Acknowledgment: We appreciate the expert statistical but more trials are required to determine the therapeu- assistance of Ignasi Gich, MD, PhD. tic role of imiquimod for infiltrative BCCs, either alone 1. Weedon D. Tumors of the epidermis: basal cell carcinoma. In: Weedon D, or in combination with other therapies. ed. Skin Pathology. London, England: Churchill Livingstone, Harcourt Pub- lishers; 1997:647-651. 2. Vidal D, Matias-Guiu X, Alomar A. Open study of the efficacy and mecha- David Vidal, MD, PhD nism of action of topical imiquimod in basal cell carcinoma. Clin Exp Dermatol. 2004;29:518-525. Xavier Matı´as-Guiu, MD, PhD 3. Beutner KR, Geisse JK, Helman D, et al. Therapeutic response of basal cell Agustı´n Alomar, MD, PhD carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad Dermatol. 1999;41:1002-1007. 4. Marks R, Gebauer K, Shumack S, et al. Imiquimod 5% cream in the treat- Correspondence: Dr Vidal, Hospital Dos de Maig, De- ment of superficial BCC: results of a multicenter 6-week dose–response trial. partment of Dermatology, Dos de Maig 301, Barcelona J Am Acad Dermatol. 2001;44:807-813. 5. Geisse JK, Rich P, Pandya A, et al. Imiquimod 5% cream for the treatment of 08025, Spain ([email protected]). superficial BCC: a double-blind, randomized, vehicle controlled study. JAm Financial Disclosure: Drs Vidal and Alomar have served Acad Dermatol. 2002;47:390-398.

(REPRINTED) ARCH DERMATOL/ VOL 143, FEB 2007 WWW.ARCHDERMATOL.COM 267

©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 6. Geisse J, Caro I, Lindholm J, et al. Imiquimod 5% cream for the treatment of two 4-mm punch biopsy specimens taken: one for ver- superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol. 2004;50:722-733. tical and the other for transverse sectioning under he- 7. Schulze HJ, Cribier B, Requena L, et al. Imiquimod 5% cream for the treat- matoxylin-eosin microscopy. The final diagnoses are sum- ment of superficial basal cell carcinoma: results from a randomized vehicle- Table controlled phase III study in Europe. Br J Dermatol. 2005;152:939-947. marized in the . After analysis, our results can be 8. Sterry W, Ruzicka T, Herrera E, et al. Imiquimod 5% cream for the treat- summarized as follows: ment of superficial and nodular BCC: randomized studies comparing low- frequency dosing with and without occlusion. Br J Dermatol. 2002;147: 1. Both vertical and transverse sections were ad- 1227-1236. equate to assess infiltrates and structure of follicles at vari- 9. Shumack S, Robinson J, Kossard S, et al. Efficacy of topical 5% imiquimod cream for the treatment of nodular BCC: comparison of dosing regimens. ous levels and to detect clues for diagnosis; Arch Dermatol. 2002;138:1165-1171. 2. Transverse sections showed more follicles; 10. Gollnick H, Guillen C, Frank RG, et al. Recurrence rate of superficial basal cell carcinoma following successful treatment with imiquimod 5% cream: 3. Vertical sections were adequate for both scarring interim 2-year results from an ongoing 5-year follow-up study in Europe. and nonscarring alopecias; and Eur J Dermatol. 2005;15:374-381. 4. Both vertical and transverse sections rendered a con- cordant diagnosis in 100% of cases. In conclusion, we found both vertical and transverse Scalp Biopsy Specimens: sections adequate for diagnosis of scarring and nonscar- Transverse vs Vertical Sections ring alopecias. Each technique offered some advantages, but neither was superior to the other. The examination of valuation of hair loss continues to be a chal- both transverse and vertical sections is beneficial but not lenge for dermatologists and pathologists. Cur- essential, and this minimal benefit must be balanced against E rent trend favors the examination of both verti- added costs and/or inconvenience for patients. cal and transverse sections of scalp biopsy specimens, although it is not clear if this is owing to opinion or evi- Carlos Garcia, MD dence. Proponents of transverse sections claim that this Eduardo Poletti, MD approach is better because one can (1) examine more follicles at various levels; (2) determine the total number Correspondence: Dr Garcia, Department of Dermatol- of terminal follicles; and (3) better appreciate infil- ogy, Oklahoma University Health Sciences Center, 619 NE trates. In contrast, those who prefer vertical sections in- 13th St, Oklahoma City, OK ([email protected]). dicate that (1) any structure of the follicle examined with Financial Disclosure: None reported. transverse sections can be seen with vertical sections; (2) very few follicles are needed to make the correct diag- COMMENTS AND OPINIONS nosis; (3) the total number of terminal follicles is the least important criterion; and (4) infiltrates can be ad- equately assessed by pattern recognition. To gather our own experience we performed a pro- Rebound Vasodilation From Long-term spective study of 276 Mexican patients whose main com- Topical Corticosteroid Use plaint was hair loss. Institutional review board approval was obtained. There were 107 male and 169 female sub- he Cutting Edge article “Successful Treatment jects ranging in age from 10 to 85 years. Each patient had of Severe Atopic Dermatitis in a Child and an T Adult With the T-Cell Modulator Efalizumab”1 Table. Biopsy Results in the May 2006 issue of the ARCHIVES discusses another medication for this disease with both short- and Finding Cases, No. long-term potential for toxic effects added to the pano- Normal 10 ply of similar medications, including azathioprine, my- Nonscarring Alopecias cophenolate, cyclosporine, and other immunomodula- Androgenetic alopecia 49 tors. As yet unknown adverse effects of efalizumab might Seborrheic dermatitis 36 preclude its long-term use. I suggest another approach Telogen effluvium 30 to the “problem” of atopy before instituting treatments Perivascular superficial dermatitis 30 with new medications. Chronic perifolliculitis 29 1 Psoriasis 14 In the case report by Weinberg and Siegfried, a dif- Trichotillomania 7 fuse erythema coupled with the typical eczematous patches Alopecia areata 7 in the popliteal area is seen in patient 1. I believe that this Scarring Alopecias diffuse erythema represents corticosteroid addiction with 2-5 Acute suppurative folliculitis 13 rebound vasodilatation, not worsening eczema. Patient Dissecting cellulitis 12 2 demonstrates “spongiotic dermatitis” on the skin bi- Lichen planus pilaris 8 opsy specimen. All of the biopsy specimens from my pa- Lupus erythematosus 8 tients who were addicted to steroids have revealed this same Folliculitis keloidalis 6 pathologic characteristic. This is not the typical patho- Central cicatricial centrifugal alopecia 3 logic presentation of atopic dermatitis. Pseudopelade of Brocq 3 Miscellaneous 11 In the past 25 years, I have treated over 1500 patients Total 276 with these problems (red skin syndrome, red scrotum syndrome, generalized severe atopy, chronic actinic derma-

(REPRINTED) ARCH DERMATOL/ VOL 143, FEB 2007 WWW.ARCHDERMATOL.COM 268