E.S. Marmur (*)

Division of Dermatologic & Cosmetic Surgery,

Department of Dermatology, The Mount Sinai Medical Center, New York, NY, USA

e-mail: ellen.marmur@mssm.edu

H. Khorasani

Department of Dermatology, The Mount Sinai Medical Center,

New York, NY, USA

Summary: Adjuvant Treatment with Imiquimod

•Current evidence does not support neoadjuvant therapy with imiquimod before Mohs micrographic surgery. Micrographic surgery requires a tumor that is growing in continuous pattern; destructive neoadjuvant treatments may yield false-negative results with independent tumor islands remaining undetected.

37.1Adjuvant Treatment with Imiquimod

Neoadjuvant therapy prior to surgery has been utilized for a variety of cancers. This method reduces the tumor burden and hence facilitates excision of many cancers, in particular, colon, prostate, and breast [1–3]. The usefulness of neoadjuvant treatment of NMSC before Mohs micrographic surgery is controversial. Imiquimod has been utilized by some surgeons as a neoadjuvant therapy in order to reduce the size of the tumor and, thus, the number of stages necessary to clear the tumor margins with Mohs micrographic surgery [4].

Imiquimod, a synthetic imidazoquinoline, has become increasingly popular, and is FDA approved, for the treatment of nonfacial superficial BCC. More recently, it is being used off-label for the treatment of SCC in situ. Imiquimod acts as an immune response modifier targeting toll-like receptors 7 and 8. Studies indicate that imiquimod exerts its antitumor activity by inducing cytokines involved in the cell-mediated immune response such as interleukin (IL)-1, -6, -8, -10, and -12; interferon-alpha; and tumor necrosis factor gamma [5].

Butler and colleagues investigated the role of imiquimod 5% cream as adjunctive therapy for primary, solitary, nodular BCC before Mohs micrographic surgery. The objective of this double-blinded, vehiclecontrolled study was to observe the effectiveness of imiquimod 5% cream in reducing the number of Mohs stages, defect size, cost of Mohs micrographic surgery, and reconstruction. Subjects applied the study medication for 6 weeks with occlusion followed by 4 weeks rest period before Mohs micrographic surgery was performed. At the end of this study, the authors did not observe any difference in the number of Mohs stages, defect size, or cost between the two groups. Only 42% of the patients in the treatment group were found histologically clear of tumor [6]. This is significantly less than the 82% imiquimod-induced histologic clearance of nonfacial superficial BCCs found previously [7].

This study’s findings are similar to that of Eigentler and colleagues in patients with nodular BCC treated using imiquimod 5% cream for 8 weeks. In 36% of these patients treated with imiquimod 5% cream, Mohs micrographic surgery 8 weeks after the completion of treatment revealed persistent BCC. Interestingly, in almost 20% of the patients with clinical clearance, there was still histopathologic evidence of the tumor

[8]. Thus, clinical clearance may not be indicative of a true, tumor-free field.

Current evidence does not support neoadjuvant therapy with imiquimod before Mohs micrographic surgery. In fact, some authors have suggested that any neoadjuvant treatment has a risk of creating skip lesions and interferes with the key principles of micrographic surgery [9]. Since the basic principle of micrographic surgery is excision of a tumor that is growing in continuous pattern, destructive neoadjuvant treatments may yield false-negative results with independent tumor islands remaining undetected.

However, there are authors that have described using adjuvant imiquimod therapy post-Mohs micrographic surgery [10]. Occasionally solid or aggressive types of BCC can also have histological superficial type of BCC at the border. Chasing these superficial tumors may cause large defects requiring reconstructions that may cause significant morbidity to the patient. In this situation, Mohs micrographic surgery is used to clear the solid or aggressive tumor, and imiquimod used as an adjuvant therapy for the remaining superficial tumor parts.

Summary: Adjuvant Treatment with Radiation

•Outcome data for high-risk SCC treated with adjuvant radiotherapy are sparse and inconclusive, even for perineural SCC. Radiotherapy may benefit some patients with high-risk SCC, particularly those with uncertain or positive surgical margins or with more advanced nerve involvement in particular cases involving the named nerves and nerves with a diameter of 0.1 mm or greater, or with clinical or radiologic evidence of nerve invasion.

37.2Adjuvant Treatment with Radiation

Adjuvant radiotherapy (ART) has been recommended in certain patients with high-risk nonmelanoma skin cancers, particularly those with perineural invasion (PNI) [11–13]. ART is also occasionally considered in patients with SCC with multiple risk factors for recurrence and metastasis. These high-risk factors include

size (>2 cm), depth of invasion (>4 mm), recurrent lesions, and in the setting of immunosuppression. Furthermore, SCCs near the parotid gland with lymphatic drainage to the periparotid lymph nodes such the ear, scalp, forehead, and lower lip are considered to be in high-risk locations [14].

The total dose and treatment regimen depends on many tumor factors including, size type, depth, and location. Radiation is usually administered over 20–30 sessions, so-called fractionations of total dosages, with cumulative doses ranging from 50 to 55 Gy. Therefore, RT is expensive and requires a significant time commitment from the patient. Radiation is not recommended in younger patients (under age of 50, because of the increased risk of radiodermatitis and scaring) or in patients with a previous history of radiation therapy [15]. Radiation is also contraindicated in patients with connective tissue diseases or genetic conditions predisposing to skin cancer (e.g., patients with Gorlin’s syndrome or xeroderma pigmentosum).

Rakkit and colleagues surveyed 795 registered American College of Mohs surgery members in order to identify variable management practices of SCC of the skin that exhibit PNI. Among the 127 respondents, 122 (96.1%) use adjuvant radiation therapy in management of SCC with PNI, with most administering it between 75% and 100% of the time if such a tumor is encountered.

Although widely used, the utility of adjuvant radiation therapy in high-risk cases is still not established by evidence-based medicine. Additionally, ART has not been shown to lengthen survival or decrease morbidity. Therefore, the use of ART for high-risk SCC varies widely among clinicians, and the utility of adjuvant therapy in such cases is unknown.

Jambusaria and colleagues conducted a systematic review of the literature, reviewing 2,449 cases of highrisk SCC in which 91 were treated with ART and concluded that outcome data for high-risk SCC treated with ART are sparse and inconclusive, even for perineural SCC. The authors concluded that ART may benefit some patients with high-risk SCC, particularly those with uncertain or positive surgical margins or with more advanced nerve involvement in particular cases involving the named nerves and nerves with a diameter of 0.1 mm or greater, or with clinical or radiologic evidence of nerve invasion [16].

This study indicated that current data are insufficient to identify high-risk features or combinations of

features associated with poor surgical outcomes in which ART may be beneficial.

A randomized double-blinded study is necessary to determine the extent of which ART reduces the risk of recurrence and metastasis in high-risk SCC. However, given the relatively low rate of recurrence of tumors with clear margins after Mohs, it may be difficult to design a study large enough to show a significant difference. It has been estimated that a study of 438 patients would be needed to detect a 10% decrease in risk of local recurrence with surgery and RT, assuming a 20% baseline risk with surgical monotherapy. Thus, further studies are needed to define the subset of patients who would benefit from ART [16].

At our institution selected patients are presented at the interdepartmental tumor board, and if deemed necessary, the patient is referred to the radiation oncologist for a consultation. Any patient with perineural, intraneural, dense perivascular, or intravascular tumor – regardless of the size of the nerve branch or vessel – is sent for an evaluation by radiation oncology but not necessarily to receive treatment. All tissue from these cases is thawed and sent for special immunostains to our senior dermatopathologists and presented at pathology conferences. Due to the lack of well-powered studies showing that there is no utility to adjuvant radiation therapy in such cases, we have a conservative approach and address each case from a collaborative view. Generally, a lowered threshold for adjuvant radiation is used in organ transplant patients with high-risk SCC.

Summary: Nonsurgical Treatment of Aggressive

Basal Cell Carcinoma

•GDC-0449, a new promising chemotherapeutic oral agent that targets the hedgehog pathway, appears to have antitumor activity in locally advanced or metastatic basal cell carcinoma. The most common side effects include muscle cramping, hair loss, and dysgeusia.

37.3Nonsurgical Treatment of Aggressive Basal Cell Carcinoma

A new and exciting chemotherapy that targets the Hedgehog signaling pathway (Hh) is being used for the treatment of basal cell carcinoma. The Hh pathway

activation has been implicated in several types of cancer such as Gorlin’s syndrome or basal cell nevus syndrome and medulloblastomas, as well as rhabdomyosarcoma.

The active ingredient in cyclopamine was discovered in 1957 when a herd of female sheep in Idaho who had been grazing on wild corn lily gave birth to multiple one-eyed lambs with malformed brains. Medical experts at the US Department of Agriculture discovered that toxins in the corn lily are powerful teratogens that alter fetal development and named the toxin cyclopamine after the one-eyed sheep. Today, cyclopamine is the key ingredient in new cancer drugs, specifically because of its activity on Hedgehog signaling pathway.

This new medication, GDC-0449 drug, is a small molecule antagonist of the Hedgehog signaling pathway (Fig. 37.1). The molecular weight of GDC0449 is 421.3 g per mole which binds to and inhibits

SMOOTHENED, resulting in the blockage of the Hedgehog signaling pathway. GDC-0449 is effective in in vitro tumor models of mutated and ligand expressing tumors. A phase I study using the drug at various dosages was first published in the New England Journal of Medicine in September 2009. The authors of this chapter are investigators in the phase II study using GDC-0449 at 150 mg PO once daily on a continuous schedule for nonsurgical basal cell carcinoma, and more studies are planned as first line therapy for metastatic colorectal cancer, recurrent ovarian cancer, and both local and metastatic advanced basal cell carcinoma. The GDC-0449 patients in these studies have advanced solid malignancies that are refractory to standard therapy or for whom no standard therapy exists (Fig. 37.2). In summary, normal Hedgehog signaling pathway inhibits downstream cellular activity. In these solid tumors,

Fig. 37.2 Extensive basal cell carcinoma. This patient exemplifies an ideal candidate for treatment with GDC-0440

there is a ligand or genetic mutation of the Hedgehog signaling pathway, allowing cellular activity to be on, and therefore tumorigenesis. The drug effectively blocks the SMO portion of the pathway and thus blocks the downstream cellular activity thereby halting tumor genesis.

Dr. Daniel D. Von Hoff et al. published the original article entitled “Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma” [17]. This was a dosing and pharmacokinetic study of the drug GDC0449 for metastatic or locally advanced basal cell carcinoma. Thirty-three patients with metastatic or locally advanced basal cell carcinoma were enrolled in the study and divided into three groups at three dosages. One group (n = 17) received 150 mg per day. The second group (n = 15) received 270 mg per day, and the third group (n = 1) received 540 mg per day. The tumor responses were assessed using the standard response, evaluation, criteria, and solid tumor (RECIST) and physical examination. The results showed that of the 33 patients, 18 had a significant response to the medication during the study period. The median duration of the study treatment was 9.8 months. In the study, imaging assessments showed improvement in 7 patients. Physical examination showed improvement in 10 patients. Both imaging and physical exam showed improvement in 1 patient. Of the 18 responders, 2 patients had complete response and 16 had partial response. Of the 15 patients who were nonresponders, 11 patients had stable disease but 4 patients progressed. In summary, 18 patients responded favorably, 11 stabilized, and 4 were treatment failures. Adverse events

noted in this phase I study included fatigue, muscle spasm, atrial fibrillation, and hyponatremia. This study concluded that GDC-0449 appeared to have promising antitumor activity in basal cell carcinoma.

The phase II study, which is ongoing currently, is a pivotal, multicenter, single-arm, global trial evaluating the efficacy and safety of GDC-0449 in patients with advanced basal cell carcinoma.

We have 4 patients enrolled in this phase II study, 2 have progressive advanced local disease and 2 have metastatic disease. So far, we have observed both clinical and radiological clearance in some of the patients. However, each patient has experienced the side effects of muscle cramping, hair loss, and dysgeusia, which is loss of taste. The phase II study is a preliminary, unpublished, ongoing global study with full enrollment of 100 patients. Data for all patients will be coming out soon. As the incidence of basal cell carcinoma increases and aggressive and metastatic cases become more common, having a nonsurgical successful treatment will be very helpful.

Summary: PEP005 Topical Gel (3-Angel Oyl

Ingenol) (Ingenol-3-Angelate)

•PEP005 is the latest of topical medications that cause local irritation and some type of immunostimulation that has been successful in treating actinic keratoses and superficial nonmelanoma skin cancers.

37.4PEP005 Topical Gel (3-Angel Oyl Ingenol) (Ingenol-3-Angelate)

PEP005 is being developed for the topical treatment of actinic keratoses and nonmelanoma skin cancers and various medicinal uses [18]. It is an active compound in the sap from Euphorbia peplus, a noninvasive medicinal plant that has a long history of community use for the topical treatment of skin cancers. Its mechanism of action has been linked to macrocyclic diterpene of three different families of similar weeds. The mechanism of action is thought to be direct toxicity plus immunostimulation. In vitro and animal models have shown that PEP005 inhibits tumor cell line