Dermatology Online Journal

Local reactions to imiquimod in the treatment of basal cell carcinoma
Yasmeen Tandon¹ MD, Robert Thomas Brodell^2,3 MD
Dermatology Online Journal 18 (9): 1

1. Case Western Reserve University-Metro Health, Cleveland, Ohio
2. University of Mississippi Medical Center, Jackson, Mississippi
3. University of Rochester School of Medicine and Dentistry, Rochester, New York

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Abstract

Basal cell carcinoma (BCC) is the most common form of skin cancer. The most commonly utilized surgical therapies for BCC are curettage and electrodesiccation (E and C) and surgical excision. Whereas surgical modalities have acceptable levels of morbidity and a high cure rate, effective non-invasive topical medical treatments of BCC are of great interest. Imiquimod is FDA approved for the treatment of superficial BCC (sBCC), actinic keratoses, and genital warts. There are several situations in which imiquimod is commonly utilized. Patients with multiple or large sBCCs may wish to avoid surgical approaches more likely to be complicated by scarring. We have also found imiquimod to be useful in elderly patients with marginal involvement of nodular BCC when the patient wishes to avoid additional surgery. Imiquimod is also useful when sBCC recurs following surgical treatments such as electrodessication and currettage and when sBCC occurs in areas that heal poorly after surgery. It is essential for physicians to explain to patients that an exuberant skin reaction is a positive indication of treatment success. Using clinical images to demonstrate the range of possible local reactions may be more effective than verbal descriptions. This minimizes the potential for premature discontinuation of therapy by patients.

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Introduction

Figure 1
Figure 1. An example of classic basal cell carcinoma

Basal cell carcinoma (BCC) is the most common form of skin cancer and accounts for approximately 80 percent of non-melanoma skin cancer [1]. According to the American Cancer Society, approximately 3.5 million basal and squamous cell skin cancers are diagnosed each year. Most of these are basal cell carcinomas. The exact number of basal and squamous cell skin cancers each year is unknown because these skin cancers are not reported to cancer registries [2]. BCC can be locally invasive but it has a low metastatic potential [1]. Red or blond hair, light-colored eyes, light skin, exposure to UV radiation, are all characteristics associated with an increased risk of BCC [3]. Basal cell carcinoma subtypes include nodular, morpheaform, superficial, infiltrative, cystic, and basosquamous forms. Nodular basal cell carcinomas appear as pearly nodules, which are often ulcerated or crusted and are often described as the “sore that will not heal.” Superficial basal cell carcinoma (sBCC) presents as an erythematous patch that is slightly scaling and well demarcated (Figure 1). Morpheaform basal cell carcinomas are ill defined and typically present with a scar-like appearance. Occasionally, basal cell carcinomas may be pigmented and can resemble malignant melanoma or seborrheic keratosis depending on the degree of pigmentation [4, 5].

Commonly utilized surgical therapies for BCC include electrodesiccation and currettage (E and C), and surgical excision [6, 7]. E and C is often selected by dermatologists for low-risk lesions. It is generally avoided in morpheaform or recurrent tumors, especially in those located at high-risk facial sites [6, 7]. Surgical excision is an excellent treatment modality that permits histopathologic margin assessment. Other treatment modalities include cryotherapy which may be utilized in the setting of multiple BCCs as an alternative to cold steel surgery. This modality, however, is less effective in large or recurrent lesions. For difficult-to-treat BCC, Mohs micrographic surgery results in high cure rates, but this modality is more time consuming and expensive [6, 7, 8].

Considering the effectiveness, cost, final cosmetic appearance, and associated morbidity, no single treatment is clearly superior [8]. Whereas surgical modalities have acceptable levels of morbidity and a high cure rate, effective non-invasive topical medical treatments of BCC are of great interest to both physicians and their patients. 5-fluorouricil 5 percent cream can be used effectively for actinic keratoses and superficial basal cell carcinoma [9]. Imiquimod 5 percent cream (1-(2-methylpropyl)-1H-imidazol [4, 5-c] quinolin-4-amin) (trade name Aldara®), a low-molecular-weight synthetic compound, was more recently approved by the United States Food and Drug Administration for sBCC, actinic keratoses, and genital warts. It is a potent inducer of interferon alfa in vivo and has potent antitumor and antiviral activity [10, 11, 12]. Recently, 3.75 percent imiquimod cream (Zyclara®) was approved by the FDA in the United States for the treatment of actinic keratoses.

Mechanism of action

Imiquimod belongs to a novel class of topical immune response modifiers. Although the mechanism of action is not fully understood, it involves the stimulation of both innate and cell-mediated immune pathways. It causes the induction of several different cytokines. These cytokines include tumor necrosis factor-α, interferon-α, and interleukin-12 from macrophages and monocytes after it binds to Toll-Like receptor-7 [13, 14]. Additionally, imiquimod stimulates other aspects of the innate immune response, including natural killer cell activity [15]. It is believed that through the induction of interferon-α, imiquimod could augment antigen presentation. This is accomplished by increasing the expression of class 1 major histocompatibility complex (MHC) proteins. In addition, interleukin-12 enhances the development of a Th1-type immune response. Improved antigen processing and presentation results from the maturation and migration of Langerhans cells [16].

Dosing ranges

A variety of dosing schedules have been recommended. The most promising dosing regimens for sBCC have been the 5 times per week and the 7 times per week regimens. Studies have evaluated regimens that are 6 and 12 week in duration and one utilized occlusion [17, 18, 19]. A 6-week treatment period may be sufficient duration for treatment because it has been observed that clearance rates for sBCC following therapy with imiquimod 5 percent cream using a 7-day per week regimen were comparable for 6 and 12 week duration. Results from a phase 3 randomized, vehicle-controlled study demonstrated histological clearance of 82 percent in sBCC lesions treated with imiquimod 5 percent cream five times per week over a period of 6 weeks and 79 percent in seven day per week dosing. These authors recommended a 5 times per week regimen for 6 weeks, which we have adopted in our practice [19].

Indications

Figure 2a	Figure 2b
Figure 2a. Multiple Basal Cell carcinomas are visible on the back. One prominent lesion is present on upper mid back (black arrow) and two lesions are present on lower mid back (White arrow) Figure 2b. Magnified view of BCC present on upper mid back (black arrow) after receiving 6 weeks of imiquimod treatment for 5 days per week

Figure 2c	Figure 2d
Figure 2c. Upper mid back lesion (black arrow) 2 months after treatment completed Figure 2d. Lower mid back lesion (white arrow) 2 months after treatment

Figure 3a	Figure 3b
Figure 3a. Patient initially presented with an erythematous patch on left lateral chin. Biopsy was done and showed superficial basal cell carcinoma. Patient was treated with imquimod five times a week for a total of six weeks. Patient presented 4 weeks after starting therapy. Lesion developed excellent inflammatory response. Exam reveals a 2 cm x 2.5 cm diameter lesion that was crusted, eroded, erythematous, and inflammatory. It had been draining and weeping. Figure 3b. 5 years after treatment patient continues to have excellent cosmetic results and no reoccurrence.

Figure 4a	Figure 4b
Figure 4a. Following a biopsy demonstrating basal cell carcinoma that extended to the margin of the tangential specimen. Imiquimod was utilized topically 5 days a week for 6 weeks. Physical examination reveals crusted, erythematous brown-black scar over a 3 cm x 2.5 cm diameter area at the left angle of the jaw. This type of aggressive inflammatory response is a good prognostic sign. Figure 4b. Some crusting is noted 2 weeks after cessation of imiquimod therapy. The skin appears to be pink and homogenously colored without signs of any persistent basal cell.

There are several clinical situations in which imiquimod is commonly utilized. Patients with multiple or large sBCCs may wish to avoid surgical approaches more likely to be complicated by scarring (Figures 2a, 2b, 2c, 2d, 3a, 3b, 4a, and 4b). It is also utilized in patients with recurrent superficial basal cell carcinoma following surgery in the distant past (Figures 5a, 5b, and 5c). Excellent cosmetic results can be achieved with this modality.

Figure 5a	Figure 5b
Figure 5a. This asymptomatic 3 x 2 cm erythematous, scaling patch recurred adjacent to the site of a superficial basal cell carcinoma treated two years previously with electrodessication and curettage. Figure 5b. Confluent bright erythema and crusting occurred following daily treatment for four weeks with imiquimod 5 percent cream.

Figure 5c	Figure 6a
Figure 5c. There has been no evidence of recurrent tumor 5 years after imiquimod treatment was completed. Figure 6a. Erythema and slight crusting are noted four weeks after treatment was initiated with imiquimod 5 percent cream daily for five days each week.

Figure 6b	Figure 7a
Figure 6b. Four months post imiquimod, complete healing has occurred with no evidence of any persistent or recurrent BCC Figure 7a. A 3 mm ulceration is present at the site of a shave biopsy of a nodular basal cell carcinoma on the nose, which demonstrated extension of the tumor to the deep margin on histopathology.

Figure 7b	Figure 7c
Figure 7b. Erythema, edema, and crusting are noted following daily treatment with imiquimod for two weeks. Figure 7c. No recurrence occurred 5 years after treatment with imiquimod was completed.

We have also found imiquimod to be useful in elderly patients in which biopsy of nodular BCC demonstrates marginal involvement following punch biopsy (Figures 6a and 6b) or shave biopsy (Figures 7a, 7b, 8a, 8b, 9a, 9b, and 9c) or when patients wish to avoid additional surgery.

Figure 8a	Figure 8b
Figure 8a. Patient presents with superficial basal cell carcinoma at the tip of the nose after daily use of imiquimod for a month. Figure 8b. Patient 6 weeks after cessation of imiquimod. He had excellent final cosmetic response.

Figure 9a	Figure 9b
Figure 9a. BCC left ala prior to treatment. Biopsy was done and tumor was found to be extending to the lateral margin. She was treated with imiquimod five times per week for a total of 6 weeks Figure 9b. Erythema can be seen present at the site of BCC. This picture was taken 3 weeks after initiation of therapy.

Figure 9c
Figure 9c. Seven years after treatment with imiquimod, the lesion has not reoccurred and has healed with good cosmetic appearance.

This non-FDA approved indication has not been studied in a large series, but when combined with careful post-operative follow-up may help some patients avoid additional surgery.

Imiquimod is also an excellent modality when sBCC occurs in areas that traditionally heal poorly after surgery, such as the lower leg. Finally, some patients prefer a less-scarring, patient-administered treatment even while accepting that cure rates may be lower. In all of these cases, careful clinical follow-up for signs of recurrent or persistent tumor is recommended for years to identify early signs of recurrence and initiate prompt surgical treatment of these tumors.

Side effects

Figure 10	Figure 11
Figure 10. There are two areas of superficial BCC on the superior left upper back and left inferior upper back. Patient was treated 5 days per week with imiquimod for total of 6 weeks. Exam reveals erythema, crusting, and edema in the skin representing an excellent inflammatory response from imiquimod. Figure 11. Patient had basal cell carcinoma of her left check which touched one lateral margin. She received daily imiquimod for a month. Exam reveals a 4 x 4 cm area of moist, red erythema, and edema of the skin.

The most common side effects of imiquimod are application site reactions. These include burning, itching, and pain at the target site. Other local skin reactions have been reported including erythema, scabbing, erosions, induration, edema, ulceration, excoriation/flaking, and vesiculation [18, 19, 20]. (Figures 10 and 11) Most patients find these side effects to be tolerable and decreasing the frequency of applications eases side effects when they are intolerable [19, 20]. Interestingly, the potential for clearing of sBCC is associated with increasing severity of erosion, erythema, and scabbing/crusting [19]. In the absence of a visible application site reaction, clearance of sBCC is unlikely. At this point, surgical intervention is recommended.

Summary

Topically applied imiquimod 5 percent cream is an excellent patient-applied medical therapy that is FDA-indicated for sBCC and is especially useful in patients with large or multiple lesions. We have also found it useful in some patients with marginal involvement after excisional surgery of nodular BCC and as a monotherapy for nodular basal cell carcinoma in elderly patients who desire to avoid surgical intervention. In these cases, it is important that patients understand and accept that imiquimod has not been definitively proven to be effective in these clinical settings. Clinical images demonstrate the range of local reactions that occur. Both patients and physicians need to be aware that these exuberant skin reactions are a positive indication of treatment success. This minimizes the potential for premature discontinuation of therapy by unprepared physicians and patients.

References

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