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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Basal cell carcinoma &#40;BCC&#41; is the most common cutaneous cancer in human history&#46; It affects over 2&#44;000&#44;000 people in the United States of America &#40;USA&#41; alone annually&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">1&#44;2</span></a> BCC accounts for more than 80&#37; of all non-melanoma skin cancer &#40;NMSC&#41; and is more prominent in Caucasian people with Fitzpatrick Type I and II skin phototypes and the number of cases worldwide are increasing every year&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">3&#44;4</span></a> Australia is currently leading the highest number of BCC in the world&#44; with incidence of 1531 per 100&#44;000 people&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Typically&#44; BCC is a relatively indolent localized condition characterized with small to medium&#44; well-defined tumors&#46; Well-established treatment options include surgical and non-surgical approaches&#46; The gold standard treatment for BCC is surgery&#44; in particular Mohs micrographic surgery &#40;MMS&#41; with safety margins&#46; Topical treatments such as imiquimod&#44; 5-fluorouracil &#40;5-FU&#41;&#44; and ingenol mebutate are usually reserved for low-risk cases such as superficial BCC&#44; small BCC &#40;diameter<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>cm&#41;&#44; or BCC in low-risk areas&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">1&#44;6</span></a> Photodynamic therapy &#40;PDT&#41; is another non-surgical option for low-risk BCC with similar efficacy to topical treatments&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">According to the National Comprehensive Cancer Network&#44; BCC can be classified into two categories&#44; low-risk and high-risk &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Although often localized&#44; in rare cases BCC can progress into a locally advanced &#40;laBCC&#41; or even rarely metastatic BCC &#40;mBCC&#41;&#44; especially when left neglected and untreated&#46; There is no established definition of laBCC&#44; but generally&#44; it is considered when the tumor penetrates deeper into the skin as well as surrounding tissues&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">1&#44;3</span></a> Metastasis in BCC is extremely rare&#44; with a rate of only 0&#46;0028&#8211;0&#46;55&#37; of all BCC cases&#46; The most common metastatic sites are bones&#44; liver&#44; and lungs&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">1&#44;3</span></a> The median survival rate of patients of mBCC is approximately between 8 months and 7&#46;3 years&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a> In cases of laBCC and mBCC&#44; the mutations in the Hh signaling pathway is more prominent compared to the classic BCC&#44; which result in more uncontrolled cell proliferation&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> In these cases&#44; surgical options are not feasible and thus non-surgical approaches should be considered&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Radiotherapy has long been a classic treatment for inoperable BCC especially for people<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>60 years old&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a> Radiotherapy produces considerably good outcome but is less effective compared to MMS&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a> However&#44; there are some disadvantages that range from cosmetic&#44; possible development of radiotherapy-induced BCC lesions&#44; and long treatment duration&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a> A review article by Dummer&#44; et al determined that surgery and radiotherapy are not suitable in conditions such as&#58; &#62;5 BCCs in patients with genetic syndromes&#44; BCCs with diameter<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>mm after 2 surgeries that are located in a critical site such as perioral&#47;periocular region&#44; inoperable BCCs that infiltrate the bone and cartilage&#44; multiple relapses of BCCs after surgery&#47;radiotherapy&#44; or patients with contraindications to general anesthesia&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">9</span></a> Other simple and cost effective techniques in treating BCC include cryotherapy and curettage&#46; These methods are less invasive and can be alternative treatments for BCC&#46; These methods relatively take less resources than radiotherapy or surgery&#44; but its use are limited especially when performed in facial areas and requires expertise as well as well-trained operators to perform in order to prevent complications such as bleeding&#44; tissue damage&#44; and post-inflammatory hypopigmentation&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">10</span></a> This prompted the need to develop more advanced and intricate approaches to deal with inoperable cases&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Research about targeted therapy utilizing systemic treatments such as the Hh signaling pathway inhibitor vismodegib and sonidegib have gained traction over the past few years&#46; Extensive research has been done to explore its efficacy and objective response rate &#40;ORR&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">8&#44;11</span></a> The ORR is based on the widely accepted Response Evaluation Criteria in Solid Tumors &#40;RECIST&#41; criteria which was first established in 2000&#44; and an updated version called the modified RECIST &#40;mRECIST&#41; guideline&#44; mainly to assess tumor changes was published in 2008&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Hedgehog signaling pathway</span><p id="par0035" class="elsevierStylePara elsevierViewall">Hedgehog &#40;Hh&#41; is a series of secreted proteins that act in a signaling pathway between the cell membrane and nucleus called the Hedgehog &#40;Hh&#41; signaling pathway&#46; The term &#8220;hedgehog&#8221; originated from the protein&#39;s first discovery observed in fruit flies &#40;<span class="elsevierStyleItalic">Drosophila melanogaster</span>&#41; during a genetic screen&#44; which showed hair-like-structure in embryos with null alleles resembling the spines of hedgehogs&#46; After its initial discovery&#44; three subsequent types of mammalian Hh ligands were discovered and were named sonic hedgehog &#40;SHH&#41;&#44; Indian hedgehog &#40;IHH&#41; and desert hedgehog &#40;DHH&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">13&#44;14</span></a> The Hh pathway plays an integral role during embryogenesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">13&#44;15</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">These proteins play important roles in early human development&#46; For example&#44; SHH is involved in limb formation&#44; central nervous system development&#44; neural tube development&#44; and formation of lungs&#44; teeth&#44; intestines&#44; and hair follicles&#44; IHH regulates bone and cartilage development&#44; and DHH holds an integral part in germ cell development and peripheral nerve sheath formation&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">13</span></a> After adulthood&#44; the activity of Hh will mostly be reduced&#44; but even then it still takes part in important roles such as homeostasis and wound healing&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">15</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The Hh signaling pathway which starts in the primary cilia&#44; is positively regulated by the membrane protein Smoothened &#40;Smo&#41;&#44; a class F G protein-coupled receptor &#40;GPCR&#41;&#44; whose activity is regulated by the membrane protein Patched &#40;PTCH&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a> There are two types of PTCH receptors&#44; PTCH1 and PTCH2&#46; In the absence of an Hh ligand&#44; PTCH will inhibit Smo activity&#44; and promotes proteolytic cleavage of full-length glioma associated oncogene &#40;GliFL&#41; to Glirepressor &#40;GliR&#41; through phosphorylation by protein kinase a &#40;PKA&#41;&#44; glycogen synthase kinase-3 &#40;GSK3&#41; and casein kinase 1 &#40;CK1&#41;&#46; GliR will then bind to Hh target gene promoters to prevent activation of Hh target genes&#44; thus turning off the signaling pathway&#46; Conversely&#44; in the presence of Hh ligands&#44; they will bind PTCH and release the inhibition of Smo&#44; initiating the signaling pathway&#46; In addition&#44; Smo is then phosphorylated by PKA and CK1&#46; The signal can then travel downstream via cytoplasmic protein complex comprised of kinesin protein &#40;Kif7&#41;&#44; suppressor of fused &#40;SUFU&#41;&#44; and GliFL to the tip of the primary cilia&#46; Gli activator &#40;GliA&#41; is then formed and will activate transcription genes&#46; This results in the release of transcription factors such as glioma associated oncogenic factors &#40;Gli&#41; &#8211; Gli1&#44; Gli2&#44; and Gli3&#41; that act as the final effector of the pathway that will result in cell differentiation&#44; proliferation&#44; and maintenance &#40;<a class="elsevierStyleCrossRef" href="#fig1">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">15&#44;17</span></a></p><elsevierMultimedia ident="fig1"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Additionally&#44; the role of TP53 gene while not a part of the Hh signaling pathway&#44; can also alter the pathway as its tumor suppressing effect can inhibit Gli transcription&#46; Therefore&#44; the activation of Hh signaling pathway can suppress the activity of TP53 gene&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">The role of Hh signaling pathway in basal cell carcinoma</span><p id="par0055" class="elsevierStylePara elsevierViewall">The aberrant activation of the Hh pathway through mutation in the PTCH1&#44; such as in the loss of function of the gene&#44; will leave no inhibition towards Smo&#44; and the subsequent release of Gli1 and formation of oncogenes as a precursor for BCC&#46; PTCH mutations is a well-known risk factor for recurrent BCC in the autosomal dominant disease of basal cell nervus syndrome &#40;BCNS&#41;&#47;Gorlin&#39;s Syndrome&#46; Furthermore&#44; factors such as UVB radiation can also induce PTCH mutation&#44; especially in type I and II skins&#46; Further analysis showed that PTCH mutations were found in 90&#37; of sporadic BCC cases&#59; mutations were found in 9q22&#46;3 locus of PTCH1 &#40;Gene ID&#58; 5727&#41; and 1p34&#46;1 locus of PTCH2 &#40;Gene ID&#58; 8643&#41;&#44; making it a suitable target for the development of targeted therapy to treat BCC&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">17</span></a> Other mutations in the pathway&#44; such as in the Smo gene are present in up to a fifth of all BCC cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">15&#44;17</span></a> Less commonly&#44; mutations in Smo or TP53 can also lead to BCC formation&#44; as mutations in these genes can also potentially induce Hh signaling pathway reactivation&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2&#44;18</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Hh pathway inhibitor</span><p id="par0060" class="elsevierStylePara elsevierViewall">Hh pathway inhibitor &#40;HPI&#41; is a class of biologic drugs indicated for the treatment of inoperable laBCC&#47;mBCC&#44; BCC that often recurs after surgeries or are not suitable for radiotherapy treatment&#46; In addition&#44; HPI can also be used to treat BCNS&#46; To date&#44; two HPIs&#44; vismodegib and sonidegib&#44; have been approved for use in the USA and Europe&#46; Out of these two drugs&#44; vismodegib is the more widely used agent&#44; being already approved for use in more than 60 countries worldwide&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">8&#44;19</span></a></p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Vismodegib</span><p id="par0065" class="elsevierStylePara elsevierViewall">Vismodegib is a first-in-class HPI which is taken orally with a dosage of 150<span class="elsevierStyleHsp" style=""></span>mg QD&#46; It acts as a PTCH substitute which binds and inhibits Smo&#44; thereby preventing uncontrolled cell proliferation and differentiation&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a> Vismodegib can be administered as monotherapy or in combination with other surgical and non-surgical treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a> The idea is that the drug will act as a neoadjuvant that can transform previously inoperable BCC cases to become operable&#46; However&#44; this can only be feasible if patients undergo long-term treatment of more than three months with good compliance which could be difficult for some patients due to the adverse effects &#40;AEs&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a> There is currently no exact duration of treatment for vismodegib&#46; Patients typically take vismodegib until there is notable improvements or until patients exhibit AEs that merit discontinuation&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">19</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Vismodegib has a high rate of concentration-dependent binding capability to plasma protein &#40;&#62;99&#37;&#41; with a half-life between 4 and 12 days and the volume distribution&#47;Vd &#40;the amount of volume of drug distributed to achieve the same concentration as it is in plasma&#41; of around 27L&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> This suggests that vismodegib is mostly concentrated in the plasma with minimal tissue penetration&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">9</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Adverse effects of the drug&#44; although mostly mild&#44; are one of the key reasons that reduce patient&#39;s compliance&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">21</span></a> Some notable AEs are muscle spasms &#40;64&#37;&#41;&#44; alopecia &#40;62&#37;&#41;&#44; dysgeusia &#40;54&#37;&#41;&#44; weight loss &#40;33&#37;&#41;&#44; asthenia &#40;28&#37;&#41;&#44; decreased appetite &#40;25&#37;&#41;&#44; ageusia&#47;hypogeusia &#40;22&#37;&#41;&#44; diarrhea &#40;17&#37;&#41;&#44; fatigue &#40;16&#37;&#41;&#44; and nausea &#40;16&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a> Mild-moderate renal impairment was also examined but further studies are needed to confirm this&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a> Vismodegib also showed teratogenic effects and is therefore contraindicated in pregnancy and two years after pregnancy&#46; Male patients are also recommended to have proper contraception when taking vismodegib&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">11&#44;21&#44;22</span></a> Possible hepatoxicity was also reported&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Alopecia is one of the most common AEs of vismodegib&#44; as inhibiting Hh signaling pathway may also affect hair follicle formation&#46; Fortunately&#44; the AE is reversible with patients reporting improvements after 6&#8211;12 months of treatment discontinuation&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a> In a case report by Villani&#44; et al&#44; the use of topical minoxidil can help reduce diffuse hair loss&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">23</span></a> Dysgeusia or loss of taste buds is also attributed to vismodegib as Hh signaling pathway affects formation and maintenance of taste buds&#44; that can lead to subsequent loss of appetite&#44; weight loss&#44; and ultimately depression&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a> Interestingly&#44; a recent review reported that the incidence of AEs in patients on treatment for more than 12 months are significantly lower compared to in the first 12 months of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In terms of drug interactions&#44; according to the EU summary of product characteristics&#44; vismodegib concentration decreases when co-administered with CYP-inducers such as carbamazepine&#44; rifampicin&#44; and phenytoin&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a> Vismodegib is also not recommended to be taken together with drugs that alter hepatic metabolism&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Information about resistance to vismodegib is still scarce&#46; There are a few case reports such as by Rudin et&#44; al on a 26-year-old male patient with medulloblastoma that initially showed tumor regression after 3 months of 150<span class="elsevierStyleHsp" style=""></span>mg QD treatment&#46; However&#44; loss of efficacy was noted after three months of treatment&#46; It was hypothesized that this resistance was due to Smo mutations that developed during treatment&#46; Another study found that a heterozygous missense mutation at position 1497 of Smo caused the switching of aspartic acid &#40;Asp&#41; for histidine &#40;His&#41; in codon 473 &#40;D473H&#41;&#46; Mutations in Smo causing less effectiveness of vismodegib&#39;s capability to bind to Smo was also mentioned by Djikgraaf&#44; et al&#46; They found 21 mutations in the Smo region&#44; in particular Smo-E518A which showed the most prominent spike in activity&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">24</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">The initial phase-1 clinical trial of vismodegib was first reported in 2009 by von Hoff et al&#46;&#44; with three different doses of 150<span class="elsevierStyleHsp" style=""></span>mg&#44; 270<span class="elsevierStyleHsp" style=""></span>mg&#44; and 540<span class="elsevierStyleHsp" style=""></span>mg QD&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">11&#44;25</span></a> A follow-up study in 2011 by Loruso&#44; et al&#46; found that the optimal dosage for vismodegib was 150<span class="elsevierStyleHsp" style=""></span>mg QD&#44; since higher dose did not increase plasma concentration&#46; The approval of vismodegib use by the EU and USA was based on two important clinical trials by ERIVANCE and STEVIE&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">4&#44;11&#44;22</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">ERIVANCE was a central review-assessed&#44; single-arm&#44; two-cohort&#44; international multicenter phase-2 clinical trial done on 104 patients &#40;33 mBCC patients and 71 laBCC patients&#41; receiving 150<span class="elsevierStyleHsp" style=""></span>mg QD oral vismodegib&#46; Initially the ORR was 30&#37; and 43&#37; ORR&#44; respectively&#46; However&#44; a follow-up study after 30 months found increased ORR to 60&#37; in laBCC and 48&#46;5&#37; in mBCC with a median duration of treatment of 26&#46;2 months for mBCC and 14&#46;8 months for laBCC&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a> The study concluded that with increased treatment duration&#44; there was increase in overall ORR&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> Disease-free survival times were 12&#46;9 months and 9&#46;3 months respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a> The final update of this trial was reported in 2017&#44; with a total trial period of 39 months and overall ORR was 60&#46;3&#37; for laBCC and 48&#46;5&#37; for mBCC&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> A total of 33 patients died with the most common cause being disease progression and adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> Average progression-free survival &#40;PFS&#41; or the amount of time during and after treatment in which patients do not experience progression of disease was 12&#46;9 months for laBCC and 9&#46;3 months for mBCC&#46; Duration of response &#40;DOR&#41; for laBCC averaged around 26&#46;2 months for laBCC and 14&#46;8 months for mBCC&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Another study&#44; STEVIE&#44; a single-arm&#44; two-cohort&#44; non-randomized &#40;non-comparative&#41; open-label study&#44; is to date the largest number of participants to date for vismodegib&#46; It involved 1215 patients consisted of 1119 laBCC &#40;208 BCNS patents&#41; and 96 mBCC patients for a total of 86 months&#46; Primary analysis found that the ORR of laBCC was 68&#46;5&#37; and mBCC was 36&#46;9&#37;&#46; Similarly&#44; in a phase-2 clinical trial&#44; 38&#37; ORR was observed in mBCC&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2&#44;19</span></a> PFS was 23&#46;2 months for laBCC and 13&#46;1 months for mBCC&#46; Furthermore&#44; DOR was 23&#46;0 months for laBCC and 13&#46;9 months for mBCC&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">A review by Brancaccio et al&#46; compiled a 21-month analysis on the efficacy of vismodegib to treat laBCC&#46; They found that the mean percentage of ORR was 47&#46;6&#37;&#44; with 25&#46;4&#37; showed partial response rate while 22&#46;2&#37; achieved complete response&#46; Additionally&#44; 34&#46;9&#37; of patients were in stable condition after consuming vismodegib and 12&#46;7&#37; experienced progression&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> A study by Chang&#44; et al found similar result for vismodegib ORR&#44; with 46&#46;4&#37; for laBCC and 30&#46;8&#37; for mBCC&#46; However&#44; the PFS and DOR were unable to be assessed due to the limited follow-up period&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Recently&#44; a study suggested that GAS-1&#44; one of the 40 Hh signaling pathway genes&#44; showed the most prominent decrease in expression after vismodegib treatment&#46; Hence&#44; quantifying GAS-1 has emerged as a potential indicator for treatment response&#46; However&#44; since this study was done with a relatively small sample size &#40;22 patients&#41;&#44; further studies in this field are needed&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">The latest study regarding vismodegib was published in 2021 in the form of VISMONEO study&#44; where it studied the efficacy and safety of vismodegib as a neoadjuvant treatment in laBCC in an open-label phase 2 trial&#46; Vismodegib was administered orally at a dose of 150<span class="elsevierStyleHsp" style=""></span>mg for 4&#8211;10 months in both operable and inoperable laBCC&#46; A total of 55 patients with the median age of 73 years old&#46; Overall response rate according to the RECIST criteria at 71&#37;&#46; &#40;95&#37; CI&#41;&#46; Vismodegib was also found to promote downstaging of laBCC especially in sites with great functional use&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Sonidegib</span><p id="par0125" class="elsevierStylePara elsevierViewall">After the initial success of vismodegib&#44; another oral HPI with similar attributes was developed&#46; Sonidegib has similar mechanism of action as vismodegib&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a> The drug is already approved by the FDA and EMA in 2015&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">20&#44;29</span></a> The drug acts by binding to the Smo protein thus suppressing Gli proteins&#44; and subsequent proliferation and tumor growth&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">To date&#44; head-to-head data of vismodegib and sonidegib is yet to available&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">9</span></a> Furthermore&#44; previous studies on vismodegib and sonidegib used different interpretations in determining ORR&#46; The ERIVANCE study of vismodegib used the RECIST criteria&#44; while sonidegib used the mRECIST criteria&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">9&#44;20</span></a> Sonidegib possesses different and interesting pharmacokinetics as compared to vismodegib&#46; The first difference is concentration dependance&#46; While vismodegib and sonidegib both have high binding capabilities &#40;&#62;99&#37;&#41; to plasma proteins alpha -1-acid cycloproteins &#40;AAG&#41; and human serum albumin &#40;HSA&#41;&#44; the binding capability in sonidegib is non-concentration-dependent&#44; while vismodegib is concentration-dependent&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">9&#44;20</span></a> Additionally&#44; sonidegib&#39;s Vd is significantly higher &#40;9170L&#41; compared to vismodegib &#40;27L&#41;&#46; This may also explain why the concentration of sonidegib on the skin is six times higher compared to when in plasma&#44; and half-life of sonidegib is 28 days as compared to only 4 days for vismodegib&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">9&#44;20</span></a> These differences prompt the possibility of efficacy discrepancies between the two drugs&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">In terms of drug interactions&#44; it is recommended to not co-administer sonidegib with CYP3A4 inhibitors&#44; as sonidegib is a substrate of CYP3A4&#46; Conversely&#44; CYP3A4 inducers should also be avoided&#44; or alternatively the dosage of sonidegib can be increased to 400&#8211;800<span class="elsevierStyleHsp" style=""></span>mg&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> A phase-1 study also found that the absorption of sonidegib is reduced when co-administered with 40<span class="elsevierStyleHsp" style=""></span>mg of esomeprazole&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> The drug is metabolized in the liver via oxidation and amide hydrolysis involving CYP enzyme&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Reports of resistance towards sonidegib are still very limited&#59; an open-label trial on laBCC showed that patients resistant to vismodegib that were treated with sonidegidib also experienced resistance to sonidegib&#44; with five out of nine patients exhibiting Smo mutations&#46; The mutations sites differed between patients&#59; reported sites included Q477&#44; D473 &#40;2 patients&#41;&#44; S533&#44; and W535&#46; These mutations resulted in the inability of sonidegib to bind to Smo&#46; However&#44; it should be noted that the small sample size underwent only short median duration of treatment &#40;5 weeks&#41; due to premature discontinuation related to adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">One of the pivotal trials that led to the approval of sonidegib was the BOLT trial&#44; a multicenter&#44; randomized&#44; double-blinded phase-1 trial conducted in 2014 that was assessed by a central review&#46; During this study&#44; it was found that the maximum tolerable dosage for the drug was 800<span class="elsevierStyleHsp" style=""></span>mg or 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>500<span class="elsevierStyleHsp" style=""></span>mg daily&#46; The study also added that 200<span class="elsevierStyleHsp" style=""></span>mg was the optimal dosage with consideration in the bioavailability&#44; efficacy&#44; and AEs&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a> A long-term 42-month study found similar efficacy to vismodegib with an ORR of 56&#46;1&#37; and 46&#46;1&#37; in laBCC patients receiving 200<span class="elsevierStyleHsp" style=""></span>mg and 800<span class="elsevierStyleHsp" style=""></span>mg dosage&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a> However&#44; for mBCC&#44; 800<span class="elsevierStyleHsp" style=""></span>mg dosage was found to produce higher ORR &#40;17&#46;4&#37;&#41; compared to 200<span class="elsevierStyleHsp" style=""></span>mg dosage &#40;7&#46;7&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a> Additionally&#44; the LDE225 trial&#44; a multicenter randomized double-blind phase-2 study found that 200<span class="elsevierStyleHsp" style=""></span>mg sonidegib produced better ORR towards laBCC with 43&#37; compared to 38&#37; in patients on 800<span class="elsevierStyleHsp" style=""></span>mg sonidegib&#44; while 800<span class="elsevierStyleHsp" style=""></span>mg was more superior for mBCC with 17&#37; ORR compared to 15&#37; in 200<span class="elsevierStyleHsp" style=""></span>mg dose&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> Furthermore&#44; this study also found the potential use of oral 800<span class="elsevierStyleHsp" style=""></span>mg sonidegib to treat BCNS&#46; In a small study of 13 BCNS patients&#44; 8 experienced complete response&#46; Topical sonidegib with 0&#46;75&#37; concentration was also explored as a mean to treat BCNS&#44; with 3 out of 13 patients experienced complete response&#46; More trials are needed&#44; but initial results showed that sonidegib is promising to treat BCNS&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">20&#44;28&#44;29</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">A review by Brancaccio&#44; et al stated the ORR based on RECIST criteria of sonidegib after an 18-month period of laBCC treatment was 60&#46;6&#37;&#44; in which 21&#46;2&#37; achieved complete response and 39&#46;4&#37; patients achieved partial response&#46; Patients with stable disease was at 30&#46;3&#37;&#44; while 1&#46;5&#37; of patients experienced disease progression&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">As with vismodegib&#44; patient compliance is an important factor impacting efficacy&#46; Compliance in patients with a lower dose is significantly higher&#44; with almost a 30&#37; difference compared to patients on higher dose&#46; Average compliance was 8&#46;9 months for 200<span class="elsevierStyleHsp" style=""></span>mg sonidegib and 6&#46;5 months in 800<span class="elsevierStyleHsp" style=""></span>mg dosage&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a> Furthermore&#44; lower dosage is attributed to less AEs&#44; with similar AEs as in vismodegib&#46; Muscle spasm is the most common AE &#40;67&#37;&#41; in patients on 800<span class="elsevierStyleHsp" style=""></span>mg sonidegib&#59; the incidence was lower &#40;49&#37;&#41; in patients on 200<span class="elsevierStyleHsp" style=""></span>mg sonidegib&#46; Alopecia and dysgeusia are the second and third most common AE &#40;43&#37; and 38&#37;&#41;&#44; but the rate is still lower compared to vismodegib &#40;62&#37; and 54&#37;&#41;&#46; Interestingly&#44; ageusia&#47;hypogeusia was not found in patients on 200<span class="elsevierStyleHsp" style=""></span>mg sonidegib&#44; while almost a fifth of patients on 150<span class="elsevierStyleHsp" style=""></span>mg vismodegib experienced them&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">6&#44;28</span></a> In addition&#44; a small number of participants on 200<span class="elsevierStyleHsp" style=""></span>mg sonidegib experienced more serious AEs such as hypertension &#40;3&#37;&#41;&#44; elevated creatine kinase &#40;3&#8211;4&#37;&#41;&#44; and increased lipase &#40;5&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a> Lastly&#44; pregnant patients are contraindicated for sonidegib as it is classified as a class-D drug that is proven to be teratogenic and can cause fetal death&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a> Thorough screening such as complete blood count and renal function&#44; as well as sufficient patient education are needed prior to administration&#46; If AEs persist&#44; treatment should be halted&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">The most recent study to combat adverse events is a limited study by Villani&#44; et al and published in 2021&#46; The aim of the single center study was to evaluate whether dosage reduction of sonidegib would reduce the AEs experienced&#46; 9 patients received daily 200<span class="elsevierStyleHsp" style=""></span>mg sonidegib treatment between 12 and 24 weeks&#44; followed with dosage adjustment of 1 dose every second day for 8&#8211;16 weeks&#46; The study found that patients experienced less severity of AEs hence increasing patient&#39;s tolerability for the long treatment of sonidegib&#46; This prompt the need for further research to confirm this method&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">31</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Role of HPI in BCC therapy</span><p id="par0165" class="elsevierStylePara elsevierViewall">Several BCC guidelines worldwide have approved the use of HPI to treat BCC&#46; This includes the National Comprehensive Cancer Network &#40;NCCN&#41;&#44; the American Academy of Dermatology &#40;AAD&#41;&#44; and the European Association of Dermato-Oncology &#40;EADO&#41;&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">NCCN Guideline in 2016 are still considering the use of systemic therapy such as HPI to treat metastatic BCC&#44; as they were still on clinical trial&#44; and a revised 2021 guideline are currently in the making&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a> In addition the AAD Guideline In 2017 have recommended a multidisciplinary approach to treat metastatic BCC&#46; The use of HPI should be considered in cases where radiotherapy is contraindicated in patients&#44; and if there are residual tumors following surgery and&#47;or radiotherapy&#44; as well if patients are inoperable&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">32</span></a> Similar with the two previous guidelines&#44; the EADO Guideline has also recommend the use of HPI to treat &#8220;difficult-to-treat&#8221; BCC such as laBCC&#44; mBCC&#44; and Gorlin Syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Role of HPI as neoadjuvant therapy for BCC</span><p id="par0175" class="elsevierStylePara elsevierViewall">Although initially approved as the primary therapy for inoperable laBCC&#44; and mBCC&#44; there are also studies for its purpose as neoadjuvant therapy to reduce extensive surgeries as well as to increase success of surgeries&#46; Patients are treated with HPIs until there are no further response and then undergone surgeries&#44; this method can significantly promote both complete and partial response as demonstrated in studies by Ching et al&#46; and Wong et al&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">37&#44;38</span></a> The first study found that the use of vismodegib as a neoadjuvant therapy can avoid bone resection in 50&#37; of subjects&#44; and the latter study on patients with ocular and orbital BCC achieved 67&#37; complete response and a notable patient was able to have orbital salvation&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">34&#44;35&#44;37&#44;38</span></a> The EADO Guideline also recommends its use as a neoadjuvant to treat laBCC&#46; However&#44; there are yet to be a randomized data available to proof its efficacy&#46; Although an initial study of 15 patients showed satisfactory result&#44; where only one patient suffered recurrency after 22 months post-surgery after consuming vismodegib for 3&#8211;6 months&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusion</span><p id="par0180" class="elsevierStylePara elsevierViewall">The HPIs vismodegib and sonidegib are novel treatments for inoperable laBCC and mBCC and is a promising treatment for BCNS&#46; Both drugs produce overall great response and can be used as either monotherapy&#44; combination with other therapies&#44; or as neoadjuvant therapy for BCC&#46; AEs of HPI&#44; although mild&#44; are often&#44; and can influence patient compliance&#46; Further studies are needed to find possible efficacy differences between the two drugs as there has yet a head-to-head study with similar assessment criteria&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflict of interest</span><p id="par0185" class="elsevierStylePara elsevierViewall">The authors declared no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Hedgehog signaling pathway"
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          "titulo" => "The role of Hh signaling pathway in basal cell carcinoma"
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          "titulo" => "Hh pathway inhibitor"
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              "titulo" => "Sonidegib"
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          "titulo" => "Role of HPI in BCC therapy"
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          "titulo" => "Role of HPI as neoadjuvant therapy for BCC"
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        10 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Conclusion"
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          "titulo" => "Conflict of interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2021-02-27"
    "fechaAceptado" => "2022-01-11"
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            0 => "Locally advanced basal cell carcinoma"
            1 => "Metastatic basal cell carcinoma"
            2 => "Hedgehog pathway inhibitor"
            3 => "Vismodegib"
            4 => "Sonidegib"
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          "palabras" => array:5 [
            0 => "Carcinoma basocelular localmente avanzado"
            1 => "Carcinoma basocelular metast&#225;sico"
            2 => "Inhibidores de la v&#237;a de Hedgehog"
            3 => "Vismodegib"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar3310" class="elsevierStyleSimplePara elsevierViewall">As one of the most common malignancies&#44; basal cell carcinoma &#40;BCC&#41; has evolved as a global burden with incidence annually rising&#44; especially in the older population&#46; Even though the condition is mostly localized&#44; the nature of the disease is destructive and can evolve as either locally advanced BCC &#40;laBCC&#41; or even more rarely as metastatic BCC &#40;mBCC&#41;&#46; There are well-established conventional treatment options for these cases&#44; including surgeries and radiotherapy&#46; However&#44; not all cases are eligible for conventional treatments&#46; Recently&#44; biologic treatment has gained a lot of attention and research&#46; This has led to the development of targeted treatment involving the hedgehog pathway inhibitor &#40;HPI&#41;&#44; a key pathogenesis in laBCC and mBCC&#46; There are currently two approved HPIs&#44; vismodegib and sonidegib to treat inoperable laBCC and mBCC&#46; This review seeks to explore the pathophysiology of hedgehog pathway behind the development of BCC&#44; and the current update of the efficacy as well as pharmacokinetics properties of HPIs that led to the ideal treatment for laBCC or mBCC&#44; either as monotherapy or in combination with other conventional therapies&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">El carcinoma de c&#233;lulas basales &#40;CBC&#41; es una de las neoplasias malignas m&#225;s frecuentes&#44; por lo que se ha convertido en una importante carga asistencial&#46; Su incidencia se incrementa anualmente&#44; especialmente en la poblaci&#243;n con mayor edad&#46; A pesar de que generalmente est&#225; bien localizado&#44; el CBC tiene la capacidad de destruir tejidos y evolucionar a un CBC localmente avanzado &#40;CBCla&#41; o incluso&#44; aunque de forma m&#225;s rara&#44; a un CBC metast&#225;sico &#40;CBCm&#41;&#46; Las opciones terap&#233;uticas convencionales en estos casos est&#225;n bien establecidas&#44; entre las cuales se incluyen la cirug&#237;a y la radioterapia&#46; Sin embargo&#44; no todos los casos son elegibles para realizar un tratamiento de tipo convencional&#46; Recientemente&#44; los tratamientos biol&#243;gicos vienen ganando una mayor atenci&#243;n y son objeto de diversos estudios de investigaci&#243;n&#46; De este modo se ha desarrollado una terapia dirigida utilizando los inhibidores de la v&#237;a de Hedgehog &#40;IVH&#41;&#44; teniendo en cuenta que se trata de una v&#237;a patog&#233;nica clave tanto en el CBCla como en el CBCm&#46; En la actualidad&#44; para poder tratar el CBCla y el CBCm no operables existen 2 IVH aprobados&#58; el vismodegib y el sonidegib&#46; Esta revisi&#243;n busca explorar la fisiopatolog&#237;a de la v&#237;a del Hedgehog responsable del desarrollo del CBC y hacer una actualizaci&#243;n en cuanto a la eficacia&#44; as&#237; como de las propiedades farmacocin&#233;ticas de los IVH&#44; caracter&#237;sticas que los convirtieron en la opci&#243;n terap&#233;utica ideal en el CBCla o en el CBCm&#44; ya sea en forma de monoterapia o en combinaci&#243;n con alguno de los tratamientos convencionales&#46;</p></span>"
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