TOPICS

Basal Cell Carcinoma A Comprehensive Review of Existing and Emerging Nonsurgical Therapies

Julien Lanoue, MD; Gary Goldenberg, MD Icahn School of Medicine at Mount Sinai Hospital, Department of Dermatology, New York, New York

Disclosure: Dr. Goldenberg is a speaker for Valeant, Leo, Genentech, and Novartis; a consultant for Valeant, LEO, Xoft, Genentech, and Novartis; and performs research for Valeant and LEO. Dr. Lanoue reports no relevant conflicts of interest.


Abstract

Basal cell carcinoma is the most commonly occurring cancer in the world and overall incidence is still on the rise. While typically a slow-growing tumor for which metastases is rare, basal cell carcinoma can be locally destructive and disfiguring. Given the vast prevalence of this disease, there is a significant overall burden on patient well-being and quality of life. The current mainstay of basal cell carcinoma treatment involves surgical modalities, such as electrodessication and curettage, excision, cryosurgery, and Mohs micrographic surgery. Such methods are typically reserved for localized basal cell carcinoma and offer high five-year cure rates, but come with the risk of functional impairment, disfigurement, and scarring. Here, the authors review the evidence and indications for nonsurgical treatment modalities in cases where surgery is impractical, contraindicated, or simply not desired by the patient. (J Clin Aesthet Dermatol. 2016;9(5):26–36.)


Basal cell carcinoma (BCC) is the most commonly occurring cancer in the world with an estimated overall lifetime risk of 20 to 30 percent.[1] In the United States alone, there are an estimated 2.8 million cases discovered annually, occurring with greatest frequency among the Caucasian and elderly populations.[2–4] Worldwide incidence rates have continued to rise in recent decades[5–9] with a particularly large increase seen among young female populations, likely secondary to lifestyle-related usage of indoor tanning and sun-seeking behavior.[11],[12] Given the vast prevalence of this disease, there is a cumulatively significant burden on overall patient well-being and quality of life.[13],[14] Similarly, there are large total health care expenditures associated with treatment of BCC.[15],[16] As such, BCC represents an important health care topic for which the authors will discuss both emerging and existing nonsurgical treatment options.

BCC is generally a slow-growing tumor for which metastases is rare, occurring in only 0.5 percent or less of cases.[17] Despite the fact that this malignancy is rarely fatal, BCC can be highly destructive and disfiguring to local tissues when presentation is delayed or treatment is inadequate. Clinically, BCCs usually appear as flesh or pink colored pearly papules and occur on the head or neck in 85 percent of cases.[18] Ulceration or telangiectatic vessels are also commonly seen.19 The current mainstay of BCC treatment involves surgical modalities such as electrodessication and curettage (EDC), excision, cryosurgery, and Mohs micrographic surgery. Such methods are typically reserved for localized BCC and offer high 5-year cure rates generally over 95 percent.[20],[21] They are, however, also associated with potential functional impairment, scarring, and disfigurement.[22] In select populations, such as the elderly, the immune suppressed, and those with poor baseline functional status as well as cases of advanced, metastatic, recalcitrant, or cosmetically sensitive disease, nonsurgical management may be a desirable alternative.[22],[23] The authors begin their discussion of such nonsurgical treatment options by first addressing localized therapies before transitioning to systemic treatments, including the newer targeted therapies. They have largely limited their discussion to include only treatments for which well-designed studies have shown successful outcomes.

Localized Therapies

Localized therapies include topical medications as well as light and radiation-based therapies. These treatment modalities may be used in cases of BCC with minimal local involvement as well as in cases with significant disease burden where surgery is impractical or simply not desired by the patient.

Imiquimod. Imiquimod functions as an immuno-modulatory drug that stimulates both the innate and cell-mediated arms of the immune system while simultaneously exhibiting direct pro-apoptotic effects on tumor cells.[24],[25] It has also been shown to inhibit the Hedgehog signaling pathway whose activation is crucial for the development and propagation of BCCs.[26] Imiquimod 5% cream is currently United States Food and Drug Administration approved in immunocompetent adults with biopsy-confirmed, primary superficial basal cell carcinoma (sBCC) that is less than 2cm in diameter and located on the trunk, neck, or extremities (excluding hands and feet). Additionally, its use is only approved when surgical methods are considered medically less appropriate and patient follow-up can be reasonably assured.[27]

Numerous studies have evaluated and provided strong evidence for the efficacy of imiquimod in the treatment of sBCC. A randomized, double-blind, vehicle-controlled, multicenter Phase 3 trial in 724 patients who received topical imiquimod 5% at intervals of 5 to 7 times per week for six weeks showed composite (histological and clinical) clearance rates of 73 to 75 percent at 12 weeks post-treatment.[28] No outcome improvement was seen in the seven times per week regimen compared to the five times per week regimen. A recent systematic review and meta-analysis of 23 randomized and nonrandomized trials estimated tumor-free survival at one year to be 87.3 percent following topical imiquimod treatment.[29] Additionally, long-term efficacy has been assessed in two multicenter, nonrandomized, open-label Phase 3 trials where imiquimod was applied five times and seven times weekly.[30],[31] Clinical clearance rates at two years post-treatment were similar in the seven times weekly trial (82%) as compared to the five times weekly trial (79%). Evaluation of five-year sustained clearance rates in the seven times weekly trial (86.9%) were also comparable to that of the five times weekly trial (85.4%).

Imiquimod has also been shown to be efficacious in treatment of nodular BCC (nBCC), but the evidence is not as strong and the results tend to be more variable and less successful compared to use in sBCC.[32–36] A Phase 3, randomized, open-label study evaluating 5% imiquimod applied three times weekly for 8 and 12 weeks showed no difference between treatment arms and a clearance rate of 78 percent following therapy.32 A smaller study using imiquimod five times per week for six weeks found complete histological clearance in all 15 periocular nBCCs at 15 weeks post-therapy.[33] A few studies have also shown good results for nBCC treated with a combination of imiquimod and Mohs micrographic surgery[37] or curettage and electrodessication.[38],[39] Long-term efficacy in nBCC has not been well evaluated but one small study of eight cases showed 75-percent clearance at five years post-therapy.[40] A three-year clearance rate of 81.8 percent for 99 nBCCs has been reported in a multicenter, parallel-group, non-inferiority, randomized controlled trial that compared 5% imiquimod to surgical therapy (98.9% 3-year clearance rate).[41]

Treatment with imiquimod is generally well-tolerated, even in sensitive areas such as the eyelid. Adverse effects are usually limited to application-site reactions and include erythema, edema, weeping, and pruritus.[33],[42],[43] The incidence and severity of these effects are reported to increase with application frequency.[43] Cosmetic outcomes are generally excellent with imiquimod therapy,30,31,33 but scarring and permanent hypopigmentation have been reported in a small percentage of cases.[40],[44]

5-Fluorouracil (5-FU). 5-FU is a pyrimidine analogue that preferentially affects DNA synthesis in neoplastic cells via inhibition of thymidylate synthase.[45] Like other topical agents, this treatment is typically reserved for treatment of superficial BCCs for which its use is FDA approved. Some experts do not recommend use of 5-FU for more aggressive BCCs due to prior studies that showed that 5-FU has a tendency to produce the appearance of superficial clinical success while tumor continues to grow unabated in deeper tissue.[46–48] There are studies, however, which report short-term success with up to 90-percent histologic clearance rates for treatment of non-superficial BCC with 5-FU.[49]

There are fewer studies regarding the efficacy of 5-FU in BCC treatment in comparison to imiquimod, but the current evidence suggests it is an equally effective short-term treatment for sBCC, although no head-to-head studies exist.[50] The package insert reports the clinical success rate of 5% 5-FU cream applied topically is approximately 93 percent based on a study of 113 easily accessible BCCs in 54 patients.[51] A more recent study of 31 biopsy-proven superficial BCCs treated with 5-FU 5% cream twice a day for up to 12 weeks showed complete histological clearance in 90 percent of lesions three weeks after completion of therapy with a mean time to cure of 10.5 weeks.[52] Intralesional therapy with a 5-FU and epinephrine gel mix has also been studied with good outcomes in one open-label, randomized study of 122 patients with biopsy-proven sBCC and nBCC where an overall efficacy rate of 91 percent at 12 weeks post-treatment was reported.[53] Similar successful results with intralesional therapy were reported in a double-blinded, randomized clinical trial of 20 nBCCs treated with therapeutic 5-FU implants where a 60 to 80 percent histologic clearance at 12 weeks post-therapy was observed depending on dosage used.[54] Despite short-term efficacy, long-term studies have shown relatively high recurrence rates for topical treatment even at concentrations higher than those currently used. A five-year recurrence rate of 21 percent was reported for 44 cases of sBCC treated topically with 25% 5-FU in petrolatum under occlusion, but a different study reported that long term-term recurrence rates were reduced to six percent in 244 cases when topical therapy with 5% 5-FU was preceded by light curettage.[55]

Adverse effects from treatment with 5-FU, such as local skin reactions including erythema, blistering, erosions, and pruritus, are commonly described.[56] Cosmetic results have been consistently reported as excellent with high patient satisfaction.[49],[52] Of note, therapy with 5-FU is contraindicated in patients with known deficiency of dehydropyrimidine dehydrogenase, as this is the primary enzyme responsible for degradation of 5-FU.[57]

Ingenol mebutate. Ingenol mebutate (IM), originally studied for treatment of actinic keratoses, is among the newest of topical agents available for the treatment of BCC. IM is a macrocyclic diterpene ester derived from the plant Euphorbia peplus.[58] This compound induces cell necrosis within a few hours of application, which is followed by an inflammatory response in the following days. Cell necrosis is believed to be secondary to mitochondrial swelling and disruption of the plasma membrane while the inflammatory response is caused by a combination of cell necrosis and IM mediated activation of protein kinase C.[59] In a Phase 2 randomized study, 60 patients with histologically proven sBCC were placed on varying dosing regimens and concentrations of IM gel or vehicle gel. Significant histologic clearance at 85 days post-treatment was observed in 63 percent of lesions when 0.05% IM gel was applied for two consecutive days.[60] The sample size was small, however, as eight treatment arms were compared. The study also concluded that IM was overall a safe therapy with low incidence rates of adverse effects, but some cases developed application-site reactions, such as erythema, scaling, crusting, swelling, blistering, and ulceration. Cosmetic outcome was not specifically assessed. Long-term studies with larger sample sizes are needed to determine true recurrence rates.

Tazarotene. Tazarotene is a retinoid compound originally developed for treatment of plaque psoriasis, but is now also approved for use in acne and photodamaged skin. Tazarotene binds specifically to retinoic acid receptors and disrupts the differentiation and proliferation of keratinocytes.[61] Its inhibiting effect on BCCs is believed to be mediated by activation of caspase-dependent apoptosis.62 In the initial open-label clinical trial of 20 subjects with sBCCs and nBCCs, 0.1% tazarotene gel applied once a day for up to eight months produced a complete clinical response in 53 percent of cases (11 of 13 sBCC and 5 of 17 nBCC).[63] A follow-up study in which tazarotene 0.1% gel was applied daily for 24 weeks to 154 sBCCs and nBCCs reported that after 24 weeks, 10.2 percent of the 108 sBCCs were unresponsive to the treatment, 25 percent showed partial regression, and 64.8 percent showed healing. Of the 46 nBCCs, 32.6 percent showed no regression, 39.1 percent showed partial regression, and 28.3 percent showed healing. At three years follow-up, 30.5 percent of the total treated lesions healed without recurrence. The only reported adverse effects of tazarotene therapy have been application-site reactions, such as erythema, erosions, pruritus, and burning.[63],[64] Cosmetic outcomes were not reported in either study. While the reported clinical clearance rates for tazarotene therapy are relatively low, the results warrant further research into compounds that may be more potent activators of the involved pathways. This therapy is also currently limited by the long treatment times, which may be problematic in achieving patient compliance.

Solasodine glycoalkaloids. The solasodine glycoalkaloids are a group of naturally occurring compounds found in plants of the nightshade family, such as aubergine.[65] Their efficacy has been proven in the treatment of actinic keratoses and photodamaged skin, but the exact mechanism of action remains unclear. It is hypothesized that these compounds disrupt cell membranes or increase expression of tissue necrosis factor.[66] A double-blind, randomized, placebo-controlled, parallel group, multicenter study compared eight weeks of twice-daily 0.005% solasodine glycoalkaloid gel to vehicle for treatment of 94 histologically confirmed BCCs of any subtype except morpheaform.66 Solasodine was found to be significantly superior to gel after eight weeks of treatment with one year clinical clearance rates of 78 percent. Results, however, were not stratified according to BCC subtype and cosmetic outcome was not assessed. Therapy was well- tolerated with no reported major systemic adverse effects other than application-site reactions, such as irritation and erosion. Further studies to determine long-term recurrence rates will be necessary before this can become a recommended therapy.

Photodynamic therapy (PDT). PDT is a well-studied, decades old treatment that utilizes light catalyzed chemical reactions to generate reactive oxygen species for tumor cell destruction. First, a photosensitizing agent, such as 5-aminolevulinic acid (ALA) or methyl aminolevulinic acid (MAL), is applied topically to the tumor. These protoporphyrin precursors are rapidly taken up by keratinocytes before being converted into porphyrin IX, a light sensitive molecule.[67] Second, the now sensitized tumor is exposed to specific light wavelengths, which react with the porphyrins and generate highly reactive oxygen singlets that mediate tumor destruction. The resulting inflammation and cytokine also enhances the innate and adaptive immune responses in immunocompetent individuals.[68] Systemic photosensitizers, such as porfimer sodium, BPD-MA and meta-tetrahydroxyphenylchlorin have been used in the past with good results, but their use has generally fallen to the wayside due to increased risk of adverse effects.[69–72]

Currently, PDT is approved for treatment of both sBCC and nBCC in Europe, Australia, New Zealand, and Canada. Although not yet an approved therapy in the United States, it is still used as an off-label treatment for BCC.[22] In regards to topical photosensitizing agents, data are mixed regarding efficacy of ALA in comparison to MAL. One study found MAL to provide deeper tumor penetration than ALA secondary to its increased lipophilicity,[73] but a small randomized study comparing the two agents in nBCC found no significant difference in outcomes.[74] A recent single center, randomized, controlled open-label study of 575 sBCCs treated with ALA-PDT compared two-fold versus one-fold light fractionation. Their results showed improved clearance rates with two-fold light exposure compared to one-fold at one year post-treatment (97% and 89%, respectively) and at five years post-treatment (88% and 75%, respectively).[75] In a different multicenter, randomized, controlled, open-label study of 118 subjects, which compared the effectiveness of MAL-PDT and cryotherapy for sBCC, it was determined that there was no significant difference in recurrence rates at five years post-therapy (22% and 20%, respectively).[76]

Studies examining PDT treatment of nBCC generally show slightly less favorable results than those seen in sBCC. One open-label, prospective, multicenter study compared efficacy of MAL-PDT in patients with sBCCs and nBCCs found that histologic clearance rates were slightly lower in nBCC compared to sBCC at three months post-treatment (75% and 85%, respectively).[77] A long-term study comparing efficacy of surgery to MAL-PDT with multiple light exposures in 105 nBCCs found five-year clearance rates of 96 and 76 percent, respectively.[78] Similar results were obtained in a randomized controlled trial comparing surgery to ALA-PDT with two illuminations in 173 nBCCs where five-year recurrence rates were 2.3 percent for surgical excision and 30.7 percent for ALA-PDT (P<0.0001).[79]

There are few adverse effects of PDT, but application-site reactions, including erythema, slight edema, and superficial erosions, have been reported.80 The most common acute side effect experienced is pain during light exposure, which has been described as a burning, stinging, or prickly sensation.81 Overall, PDT also offers excellent cosmetic results, significantly superior to that of surgical modalities, albeit at the cost of higher recurrence rates.[78],[82],[83] Contraindications for PDT include a history of porphyria or allergy to photosensitizing agents.[84]

Laser therapy. Laser therapy is not yet an FDA-approved treatment for BCC, but it has been used with reported success as an off-label treatment. For dermatologic considerations, laser therapy uses monochromatic light to ablate the most superficial layers of the skin. In the past, continuous wave lasers were used, but this had a greater potential to cause nonspecific thermal damage and thus result in atrophic or hypertrophic scarring.[85] In the present, pulsed lasers are more commonly used, which provide quick, high-intensity bursts of light to more selectively vaporize the superficial skin layers. One retrospective study examining the use of superpulsed CO2 lasers in 140 patients with either sBCC or nBCC via histologic examination from scrapings done prior to therapy, during therapy, and immediately after therapy reported no histological evidence of BCC after therapy in any of the patients studied.[86] It was also reported that there were no recurrences during the three-year follow-up window. While this study reported significant success with both sBCC and nBCC, a related study on 51 BCCs examined histologically after CO2 laser treatment reported that only sBCCs could be reliably ablated when lesions were lasered down to a depth of the middle dermis or deeper.[87] Of note, this latter study also reported that laser therapy was at least three times as fast as surgical therapy.

Therapy with neodymium (Nd)-based lasers, a more superficially penetrating laser often used for hair removal, has been reported to have excellent short-term results according to a large retrospective study.[88] Of 2,719 facial BCCs treated with a pulsed Nd laser, only 1.8 percent recurrences were reported with follow-up between three months and five years. Of the 627 BCCs treated with a neodymium: yttrium aluminium garnet (Nd:YAG) laser, 2.5 percent recurrences were reported in the same follow-up period. Notably, the penetration depth of pulsed Nd laser radiation did not exceed 5mm, and thus this modality should only be used for tumors less than 2 to 3mm from the skin surface. Adverse effects include reactive hyperemia, edema, and slight soreness in the first few days post-therapy. Cosmetic results were reported as acceptable.

Pulsed dye lasers (PDL) are typically used to treat vascular lesions by targeting hemoglobin within blood vessels to induce thermolysis. More recently, they have been studied as treatments for BCC that work by destroying tumor microvasculature.[85] A recent double-blind, randomized, placebo-controlled trial examining the efficacy of four 595nm PDL sessions over a 12-week period on 100 sBCCs found complete clinical and histologic remission at six months post-treatment in 78.6 percent of cases compared to 4.5 percent of cases receiving sham treatment.[89] A smaller study of 20 biopsy-proven BCCs of varying subtype used the same treatment modality and found complete histologic and clinical clearance in 90 percent of cases at 12 months post-treatment regardless of BCC size or histologic subtype.[90] Overall patient satisfaction with this modality is reported to be high, but excellent cosmetic outcome is occasionally limited by the adverse effect of persistent hypopigmentation.[89]

Laser therapy has also been studied as a pre-treatment to photodynamic therapy, as it was hypothesized that superficial tumor ablation would allow for greater tumor penetration of the photosensitizing agent and thus result in lower recurrence rates. A large randomized controlled study examining this relationship compared therapy with ALA-PDT, erbium (Er):YAG laser, and a combination of Er:YAG laser prior to ALA-PDT in the treatment of recurrent nBCC.[91] They reported the following one-year recurrence rates (p<0.001): ALA-PDT: 5.15 percent, Er:YAG laser: 8.25 percent, and combination therapy: 1.03 percent. This study also reported superior cosmetic results in combination therapy as compared to monotherapy with PDT or Er:YAG laser, which had equal cosmetic outcomes.

Overall, monotherapy with lasers is lacking in randomized clinical trials, but there is good anecdotal evidence for its success in superficial BCCs. Caution should be used with deeper lesions, such as nBCC, where one may want to consider combination therapy with PDT. Adverse effects are generally negligible and cosmetic outcomes are reported as moderate to good. Radiotherapy. Radiotherapy treatment for BCC can be divided into two broad classes: conventional external radiotherapy, also known as teletherapy, and internal radiotherapy, also known as brachytherapy. External radiotherapy uses x-rays or electron beams provided by a radiation source distant to the area being treated. Conversely, internal radiotherapy is when the radiation source is closely applied to or even implanted into the area being treated. Both modalities make use of high-energy electromagnetic waves to induce genetic damage, eventually leading to cell lysis and tumor destruction.

Teletherapy has proven efficacy in treatment of BCC with reported five-year control rates of 92 percent in one study of 389 superficial-to-advanced BCCs treated with a variety of external radiation therapies.[92] Similar results were obtained by a large, randomized, controlled, multicenter study, which examined the use of teletherapy in the treatment of biopsy-proven nBCC and sBCC.[93] This study reported two-year histologic recurrence rates of only four percent (data not stratified by cancer type). Given these high rates of success, teletherapy is generally considered the second most effective treatment for BCC behind surgery.[65] There are considerable drawbacks to therapy, however, as external ionizing radiation has significant penetration capability and can result in inadvertent damage to surrounding tissue and organs. Adverse effects, such as tissue necrosis, skin atrophy, pigmentation, teleangiectasias, and new primary tumor development have been reported.[94] Radiotherapy scars also have the unfortunate tendency to worsen over time unlike surgical scars, thus leading to cosmetic results that are often worse than surgical therapy.[23] As a result of these effects, teletherapy is often only recommended for patients over the age of 50.

The application of near-source radiation in brachytherapy can be achieved through a variety of techniques and dosing-rates. Interstitial brachytherapy is one such means which is accomplished through the surgical implantation of capsules filled with radioactive materials directly into tumor sites. Surface-mold brachytherapy involves the creation of a pliable mold filled with radioactive material that conforms topographically to tumor surfaces. Both techniques have been used with success in the past where large randomized controlled trials and prospective cohort studies reported long-term recurrence rates similar to that of external radiation (2.2–8.8%) for the treatment of sBCC and nBCC.[95–97] More recently, electronic brachytherapy (EBX) has been gaining popularity as a form of high-dose radiation brachytherapy. EBX is a recently developed technology that is FDA-cleared to treat breast, vaginal, endometrial, cervical, and nonmelanoma skin cancer.[98] This modality has the major advantage over other forms of radiotherapy in that it does not require the use of radioactive isotopes or dedicated treatment vaults. Initial study results where EBX was used to treat 81 BCCs reported no recurrences at an average of 10 months follow-up.[99] The most commonly reported adverse effects were application-site dermatitis and pruritus. Cosmetic results were generally reported as excellent, but long-term hypopigmentation was noted as a possible late adverse effect. While these initial results are encouraging, longer term and repeat studies will be needed to determine and validate this EBX’s true efficacy.

The major advantage of brachytherapy over teletherapy is the ability to minimize radiation to healthy tissue while still achieving successful tumor destruction. This advantage can be accentuated when low-dose radiation or beta-emitting isotopes are used, but this comes at the price of longer treatment times.94 The reduced penetration potential of brachytherapy, however, also means that sufficient radiation cannot usually be delivered to depths greater than 2mm, thus making the treatment of deep or infiltrative tumors impractical.[94] Overall, brachytherapy is considered to be well-tolerated by patients, but adverse effects at the application site are common and include inflammatory exudative desquamation, erythema, and edema.[94] Cosmetic outcome is generally acceptable, but inferior to that of surgical excision with reports of occasional scarring, skin necrosis, and hypopigmentation.[94],[95],[100]

Systemic Therapies

Systemic therapies include classical chemotherapy as well as the newest class of targeted medications. These treatment modalities are typically reserved for metastatic BCC (mBCC) or locally advanced BCC (laBCC) for which surgery and radiation has failed or is not an option.

Given the systemic nature of these treatments, there are generally greater risks of adverse effects, but recent studies have relatively good safety and efficacy profiles for the targeted therapies.

Hedgehog pathway inhibitors. Most BCCs contain genetic alterations in the Hedgehog (Hh) signaling pathway, which subsequently results in basal cell proliferation. The Patched gene (PTCH), which is mutated in 90 percent of sporadic BCCs,101,102 codes for a transmembrane protein that normally inhibits Hh pathway activation by binding to and inhibiting the Smoothened (Smo) protein, a natural Hh pathway activator.[103],[104] Mutations in PTCH are also seen in basal cell nevus syndrome (BCNS), a condition where patients are predisposed to developing hundreds of BCCs.[105] Given this information, the recently developed Hh pathway inhibitors are an intriguing and novel therapeutic option capable of specifically targeting BCCs.

Vismodegib is a first-in-class Smo antagonist and Hedgehog pathway inhibitor (HHI) that has been FDA approved for use in metastatic BCC, laBCC that has recurred following surgery, or laBCC in those who are not candidates for surgery or radiation. A multicenter, nonrandomized, Phase 2 clinical trial studied the efficacy of oral vismodegib 150mg daily in patients with mBCC or laBCC with inoperable disease and determined that the overall objective response rate (ORR) in the mBCC group was 30 percent.[103] All responses were partial responses (PR), but these results were significantly greater than the null hypothesis of 10 percent (p=0.001). The ORR in the laBCC group was 42.9 percent, including 13 complete responses (CR) and 14 PR, which was significantly greater than the null hypothesis of 20 percent (p<0.001). Additionally, 64 percent of patients in the mBCC group and 38 percent of patients in the laBCC group showed stable disease as the best response. In sum, 94 percent of mBCC patients and 81 percent of laBCC patients showed improvement or stability in their disease state while on vismodegib. In a recent follow-up report, the investigators determined that the median duration of response increased in both cohorts (mBCC = 14.8 mo; laBCC = 26.2 mo) from the median determined at the time of primary analysis (mBCC = 7.6 mo; laBCC = 12.9 mo).106 Similar results were obtained by an open-label, multicenter, two-cohort study where patients with laBCC or mBCC inappropriate for surgery or radiotherapy received 150mg vismodegib daily until disease progression or intolerable toxicity.107 Of the 62 patients with laBCC, the ORR was 46.4 percent and of the 57 patients with mBCC, the ORR was 30.8 percent.

Vismodegib has also shown success in treatment of other BCC populations. A randomized, double-blind, placebo-controlled, Phase 2 trial compared vismodegib 150mg once daily to placebo for a maximum of 18 months in patients with BCNS and 10 or more surgically eligible BCCs present at the time of study entry or removed during the prior two years.[108] Compared to placebo (n=15), vismodegib (n=26) significantly reduced the rate of new BCCs per group (vismodegib: 2/26; placebo: 29/15; p<0.001) with an average follow-up of eight months. A significant reduction in average size, as determined by the sum of the longest diameters, of existing BCCs was also seen (vismodegib: -65%; placebo: -11%; p=0.003). Given the ability of vismodegib to shrink tumors, several studies have also examined the use of vismodegib as a neoadjuvant therapy prior to surgical removal. One clinical trial of 15 patients showed a 27-percent reduction in the surgical defect area (p=0.006) as compared to baseline following 3 to 6 months of vismodegib.[109] Recurrence was only seen in one tumor at 17 months post-surgery. Preliminary results from a similar clinical trial where vismodegib 150mg was given to 24 patients with one operable nBCC on the scalp, head, and neck, or cape area for 12 weeks prior to surgery reported a clinical response in 23 (96%) of the patients, including 10 (42%) with complete histological clearance.[110]

Adverse effects from vismodegib treatments are widely reported, but manageable, and include muscle spasm, alopecia, dysgeusia, weight loss, and fatigue.[103],[111],[112] It is believed that most of these side effects are a direct result of Hh pathway inhibition, a so-called “class effect,” and are thus unlikely to be circumvented by future drugs similarly inhibiting this pathway.[113] There are also concerns over tumor resistance to HHIs, either in patients who were initially unresponsive (primary resistance) or who showed response, but later developed regrowth (secondary, acquired resistance). In one retrospective study of 28 patients with laBCC or mBCC, 21 percent developed at least one tumor regrowth while undergoing continuous vismodegib treatment, with a mean time to detected regrowth of 56 weeks as determined by clinical examination.[107] Further research is necessary to better determine the mechanisms behind resistance and to also identify novel drugs or combination strategies that may overcome such resistance. Nevertheless, vismodegib has provided a group of patients with previously limited treatment choices a new therapeutic option with significant clinical response rates (Figure 1).

Given the success of vismodegib, there is active ongoing research into other HHI compounds. Sonidegib is a Smo antagonist that recently met its Phase 2 study endpoints. This trial assessed the efficacy of two oral doses of sonidegib, 200mg and 800mg, in patients with laBCC or mBCC that was not amenable to surgery or radiation.114 The 200mg group’s median exposure was 8.9 months and the ORR for laBCC (n=66) was 47 percent and the ORR for mBCC (n=13) was 15.4 percent. The 800mg group’s median exposure was 6.5 months and the ORR for laBCC (n=128) was 35.2 percent and the ORR for mBCC (n=23) was 17.4 percent. All reported ORRs were determined to be significant (p <0.05). Adverse effects were reported with less frequency overall compared to vismodegib, but included similar effects, such as muscle spasms, dysegusia, weight loss, and nausea. Sonidegib has also demonstrated success as a topical agent in a double-blind, randomized, vehicle-controlled, intraindividual study where eight patients with NBCS and a total 27 BCCs were treated twice daily with 0.75% sonidegib cream or vehicle for four weeks.115 Of the 13 BCCs treated with sonidegib, three showed CR, nine showed PR, and only one showed no clinical response. The vehicle produced PR in one lesion, but no clinical response in any of the other 13 treated BCCs. Application of sonidegib cream was reported to be well-tolerated with no skin irritation. Further research is necessary to determine the long-term efficacy of sonidegib, but these initial preliminary results are promising.

Active research is currently underway into compounds that may accomplish Hh pathway inhibition by affecting targets more downstream of Smo. Itraconazole is one such compound that works by inhibiting Gli, a transcription factor that is activated following Smo agonism. A Phase 2 trial of oral itraconazole in 19 patients with one or more BCC tumors >4mm in diameter reported a 45-percent decrease in cell proliferation (p=0.04), a 65-percent reduction in HH pathway activity (p=0.03), and a 24-percent reduction in tumor area.[116] Fatigue was reported as an adverse effect in one patient and congestive heart failure in another. Although these initial results are less successful than that of the Smo antagonists, they provide a basis for further research into alternative mechanisms of Hh pathway inhibition. Some other HHIs currently in Phase 1 studies to keep an eye on include LEQ 506, BMS-833923 (XL139), Taladegib (LY2940680), and TAK-441.[117]

Chemotherapy. Given the relative rarity of metastatic or significantly advanced BCC, chemotherapeutic regimens have not been well-studied with prospective or randomized clinical trials. According to a recent literature review of all published metastatic basal cell cases from 1981 to 2011, cisplatin-based chemotherapies are most commonly used systemic regimens.[118] This therapy has demonstrated varied clinical outcomes, from minimal response to complete remission.[119–127] Such therapy, however, comes with significant adverse effects. Notably, cisplatin is associated with significant renal toxicity and has also been reported to cause severe nausea, vomiting, diarrhea, alopecia, joint pain, loss of balance, tinnitus, edema, and fatigue.[119–127] With the recent advent of the more targeted therapies discussed above, chemotherapy should be reserved as a second-line treatment for those who fail to respond or develop resistance to HHIs.

Conclusion

Given the variety of nonsurgical treatment options available for BCC (Table 1 ), physicians must take into account numerous factors in order to determine which therapy, or combination of therapies, would best meet the goals of the patient. As a general rule of thumb, nonsurgical modalities, such as topical creams and phototherapies, are superior to surgical therapies for non-advanced BCCs in cosmetically sensitive areas, albeit at the cost of higher recurrence rates and longer treatment times. Additionally, nonsurgical therapy is usually more effective for superficial BCCs than nodular BCCs. In cases of deep or infiltrating BCC, nonsurgical modalities should be used with caution and clinicians may want to consider a combination of therapies to minimize recurrence. For cases of advanced BCC, physicians may turn to radiotherapy or Hedgehog pathway inhibitors. These latter treatment modalities may one day prove efficacious in treatment of less advanced BCCs in the form of electronic brachytherapy or topical HHIs, but further research is needed to verify and determine the long-term efficacy and safety of such measures.

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