[REVIEW]
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
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.)
asal 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 decades5–9 with a particularly large increase seen among young female populations, likely secondary to lifestylerelated 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 wellbeing 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
B
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 welldesigned 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
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. ADDRESS CORRESPONDENCE TO: Gary Goldenberg, MD, Icahn School of Medicine, at Mount Sinai Hospital, Department of Dermatology, 5 East 98th Street 5th Floor, New York, NY 10029; Email: [email protected]
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burden where surgery is impractical or simply not desired by the patient. Imiquimod. Imiquimod functions as an immunomodulatory drug that stimulates both the innate and cellmediated 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 biopsyconfirmed, 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 posttreatment.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 metaanalysis of 23 randomized and nonrandomized trials estimated tumor-free survival at one year to be 87.3 percent following topical imiquimod treatment.29 Additionally, longterm 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 surgery37 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, noninferiority, 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 shortterm 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 openlabel, 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 fiveyear 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
[May 2016 • Volume 9 • Number 5]
27
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 28
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 welltolerated 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 5aminolevulinic 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, BPDMA 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,
[May 2016 • Volume 9 • Number 5]
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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
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
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.)
asal 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 decades5–9 with a particularly large increase seen among young female populations, likely secondary to lifestylerelated 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 wellbeing 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
B
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 welldesigned 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
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. ADDRESS CORRESPONDENCE TO: Gary Goldenberg, MD, Icahn School of Medicine, at Mount Sinai Hospital, Department of Dermatology, 5 East 98th Street 5th Floor, New York, NY 10029; Email: [email protected]
26
[May 2016 • Volume 9 • Number 5]
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burden where surgery is impractical or simply not desired by the patient. Imiquimod. Imiquimod functions as an immunomodulatory drug that stimulates both the innate and cellmediated 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 biopsyconfirmed, 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 posttreatment.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 metaanalysis of 23 randomized and nonrandomized trials estimated tumor-free survival at one year to be 87.3 percent following topical imiquimod treatment.29 Additionally, longterm 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 surgery37 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, noninferiority, 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 shortterm 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 openlabel, 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 fiveyear 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
[May 2016 • Volume 9 • Number 5]
27
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 28
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 welltolerated 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 5aminolevulinic 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, BPDMA 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,
[May 2016 • Volume 9 • Number 5]
28
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
