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Identifying locally advanced basal cell carcinoma eligible for treatment with vismodegib: an expert panel consensus Ketty Peris*,1, Lisa Licitra2, Paolo A Ascierto3, Renzo Corvò4, Marco Simonacci5, Franco Picciotto6, Giulio Gualdi7, Giovanni Pellacani8 & Armando Santoro9
ABSTRACT Basal cell carcinoma (BCC) is the most common skin cancer worldwide. Most occur on the head and neck, where cosmetic and functional outcomes are critical. BCC can be locally destructive if not diagnosed early and treated appropriately. Surgery is the treatment of choice for the majority of high-risk lesions. Aggressive, recurrent or unresectable tumors can be difficult to manage. Until recently, no approved systemic therapy was available for locally advanced or metastatic BCC inappropriate for surgery or radiotherapy. Vismodegib provides a systemic treatment option. However, a consensus definition of advanced BCC is lacking. A multidisciplinary panel with expertise in oncology, dermatology, dermatologic surgery and radiation oncology proposes a consensus definition based on published evidence and clinical experience. Basal cell carcinoma (BCC) is the most common form of skin cancer worldwide, with an incidence that varies geographically from >1000/100,000 in Australia to 1/100,000 in some African countries, and an increasing trend in many European countries [1] . However, it is difficult to appreciate the scale of the problem because often BCC is not reported in tumor registries. A recent estimate of the BCC incidence in the UK, based on histopathology databases, indicates that the actual number may be twice of that reported in the National Tumor Registry [2] . In the USA, analysis of a private healthcare database with 14 million enrollees revealed an estimated BCC incidence of approximately 560/100,000 in 2010 and an incidence of locally advanced BCC (laBCC) of approximately 8/100,000, corresponding to nearly 30,000 new cases of laBCC [3] . BCCs usually are slow-growing skin tumors that originate from long-lived progenitor cells in the interfollicular epidermis [4] or from hair follicle stem cells [5] . Risk factors for BCC include exposure to ultraviolet (UV) radiation, especially in subjects with fair skin and blue/green eyes, advanced age, prolonged immunosuppression or a personal or family history of skin cancer [6] . Consistent with the role of UV radiation exposure, 80% of BCCs occur on the head or neck [7] . Development of BCC is also associated with several hereditary syndromes including basal cell nevus syndrome, Bazex–Dupré–Christol syndrome, Rombo syndrome, Oley syndrome and xeroderma pigmentosum [8] .
KEYWORDS
• basal cell carcinoma • locally advanced basal cell carcinoma • therapy • vismodegib
Department of Dermatology, Catholic University of Rome, Rome, Italy Head & Neck Medical Oncology Unit, Fondazione IRCCS Istituto Tumori, Milan, Italy 3 Melanoma Cancer Immunotherapy & Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione ‘G Pascale’, Naples, Italy 4 Department of Radiation Oncology, IRCCs San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, University of Genoa – DISSAL, Genoa, Italy 5 Dermatological Unit, Macerata Hospital, Macerata, Italy 6 Section of Dermatologic Surgery, Department of Oncology & Haematology. AOU Città della Salute e della Scienza, Turin, Italy 7 Department of Dermatology, Spedali Civili Brescia, Italy 8 Department of Dermatology, University of Modena & Reggio Emilia, Modena, Italy 9 Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS, Rozzano (Milan), Italy *Author for correspondence: Tel.: +39 06 30 15 4227/4221; Fax: +39 06 30 16 293; [email protected] 1 2
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Review Peris, Licitra, Ascierto et al. The first-line treatment for BCC is surgical excision, whereas radiotherapy may be indicated when surgery is not appropriate or is contraindicated. Other nonsurgical techniques (e.g., photodynamic therapy and topical therapies) may be useful in certain cases [9] . BCC can be locally invasive if neglected, recurrent and/or an aggressive subtype; in rare cases, it can metastasize [7] . Tumors may progress to the point that surgical excision is no longer possible or would result in unacceptable disfigurement or loss of function (Figures 1–3) . Patients who are not good candidates for surgery may benefit from radiotherapy. However, large or multifocal lesions are not necessarily indications for radiation therapy. Further radiotherapy for lesions recurring after radiotherapy is not advisable due to the potential for acquired radioresistance. Approximately 1% of patients with BCC develop advanced disease [10] . Until recently, no systemic therapy was approved for treatment of advanced BCC, and in the past, patients were treated mainly with cisplatin alone or in combination with other drugs, with limited efficacy and considerable side effects [11] . ●●Vismodegib
Most BCCs harbor genetic alterations that inappropriately activate hedgehog signaling. This pathway is normally controlled by PTCH1,
Figure 1. A basal cell carcinoma on the left temporal-parietal region of an 80-year-old patient. This tumor had recurred multiple times after surgical excision with margin control.
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which inhibits the signaling activity of the smoothened homolog (SMO) and subsequent activation of downstream target genes. Loss of PTCH1 function, or more rarely activating mutations in SMO, drive uncontrolled proliferation in sporadic BCC and in BCC associated with basal cell nevus syndrome [12–14] . Thus, this pathway is an attractive therapeutic target in BCC. Vismodegib is a first-in-class, small molecule inhibitor of SMO that was approved in 2012 in the USA and conditionally approved in the EU for adult patients with symptomatic metastatic BCC or laBCC inappropriate for surgery or radiotherapy. A Phase I trial in 33 patients with inoperable tumors or tumors for which surgery was inappropriate showed responses in 19/33 patients, with a median response duration of 12.8 months [15,16] . The pivotal, nonrandomized Phase II ERIVANCE BCC trial enrolled 104 patients with metastatic BCC or laBCC. Patients with laBCC had inoperable tumors or surgery was inappropriate due to multiple recurrences, low likelihood of cure or high probability of substantial disfigurement. All patients received vismodegib 150 mg once daily until disease progression, intolerable toxicity or withdrawal from the study. Objective response rates (ORR) determined by an independent review were 43% (27/63) for laBCC and 30% (10/33) for metastatic BCC. Complete responses were observed in 13 patients (21%). Median response duration was 7.6 months [17] . These response rates were confirmed in an open-label expanded access study of 119 patients that revealed ORRs of 46.4% in patients with laBCC and 30.8% in patients with metastatic BCC [18] . The study was discontinued upon US FDA approval of vismodegib after a median 5.5 (range: 0.4–19.6) months of treatment. The most common adverse events were similar to those reported in previous studies of vismodegib, and comprised muscle spasms (70.6%), dysgeusia (70.6%), alopecia (58.0%) and diarrhea (25.2%). Most of these were grade 1 or 2. One treatment-related grade 3 adverse event was reported (muscle spasms); two patients discontinued because of drug-related adverse events. Long-term treatment with vismodegib has not been investigated thoroughly, and few patients have been treated for longer than 24 months. Not all patients tolerate therapy, and treatment duration may be limited by intolerable toxicity.
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Basal cell carcinoma eligible for vismodegib This has important implication because vismodegib does not eradicate the disease, and tumors regrow when therapy is stopped [19] . Another common reason for interrupting therapy is disease progression. Resistance to vismodegib has been reported [20] and mechanisms of acquired resistance have been described [21] . Neoadjuvant therapy with vismodegib may provide a bridge to curative therapy [22] . Availability of the first approved systemic therapy for advanced BCC provides a treatment for patients who are no longer candidates for surgery or radiotherapy. A consensus definition of advanced BCC is currently lacking [23] . We propose criteria based on published evidence and clinical experience for defining laBCC inappropriate for surgery or radiotherapy. Methods A nine-member multidisciplinary panel with expertise in oncology, dermatology, dermatologic surgery and radiation oncology met to present and discuss available evidence and their clinical and/or research experience with advanced BCC. A draft consensus document defining laBCC not amenable to local therapy emerged. Differences were resolved through discussion and a consensus was defined as the majority position. Subsequent rounds of revision were carried out through electronic mail and the final version was discussed and approved in teleconference. Management of basal cell carcinoma When choosing the most appropriate therapy for BCC, factors including tumor location and size, histological subtype and whether the lesion is recurrent must be considered. Further considerations include the patient’s ability and willingness to tolerate surgery and reconstruction, and suitability for radiotherapy. Currently, surgical excision is recommended as first-line treatment in nearly all cases of BCC [24–29] . The goal of surgery is to obtain a cure by excision with clear lateral and deep surgical margins, while sparing function and achieving a good cosmetic outcome. Most nodular or superficial BCCs occurring outside of high-risk areas can be surgically removed under local anesthesia using 3-4 mm surgical margins with excision down to subcutaneous fat [30] . On the other hand, management of large, infiltrative or recurrent tumors may require extensive resection, sometimes under
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Figure 2. Multiple basal cell carcinomas on the face. (A) A patient with multiple lesions on the face: each of the individual lesions is amenable to surgical removal, but overall, surgery is not indicated. (B) Detail of multifocal lesions that appeared near the surgical scar of an extensive and histologically radical resection. Patient not suitable for radiotherapy due to broad extension.
general anesthesia, followed by arduous reconstructive procedures. In such cases, lateral margins may vary from 5 to 15 mm or more depending on tumor size, location and histological subtype, whereas deep margins are determined by the depth of penetration and nature of the underlying tissue [30] . Postoperative assessment of margins is mandatory and in some high-risk tumors, intraoperative assessment of margins may be indicated. Mohs micrographic surgery (MMS) and its variants (e.g., ‘slow’ Mohs surgery) allow systematic assessment of lateral and deep margins, with further staged excision of involved areas as required. MMS generally provides cure rates of 97–99% for primary BCC and 92–95% for previously treated tumors [31–33] . Randomized clinical trials comparing surgical excision and MMS reveal that both techniques provide excellent control rates for primary tumors [34,35] . MMS had better 5-year recurrence rates when treating recurrent tumors. Moreover, MMS has the advantage of sparing healthy tissue, which is important when treating lesions in cosmetically and functionally sensitive areas. MMS may be particularly suitable for recurrent periorificial BCC. BCCs are generally radiosensitive cancers [36] . Short treatment courses with superficial X-rays, γ-rays or an electron beam with addition of a 5–10 mm margin around the tumor results in high cure rates, especially for early lesions [37] . Radiotherapy may be used with radical, adjuvant (surgery with close or involved margins) or palliative intent, but is not indicated
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Review Peris, Licitra, Ascierto et al. patients hypersensitive to radiation, such as those with basal cell nevus syndrome. Radiotherapy is contraindicated also for tumors involving cartilage or bone, due to the risk of chondro- or osteoradionecrosis, and should be used with caution in patients with connective tissue diseases such as scleroderma or lupus erythematosus. ●●Tumor-specific factors influencing
appropriateness of surgery
Figure 3. Basal cell carcinoma recurrence after three successive surgical excisions and one cycle of radiotherapy. There is infiltration of the galea and periosteum.
for multifocal BCC or extensive tumors with bleeding or infected areas. Radiotherapy is particularly useful for inoperable BCC involving the tip of the nose, lip commissure, inner canthus of the eye or eyelid [30] . Tumors near radiosensitive organs at risk of severe acute or late toxicities require treatment with radiotherapy equipment capable of providing a steep dose gradient between the BCC and surrounding healthy tissue. Thus, referral may be indicated if such equipment and expertise are not available. Potential side effects occurring at the irradiated site include skin atrophy, alopecia and telangiectasia. Because of the risk of secondary tumors, radiotherapy is indicated for older patients (>70 years), and is contraindicated in
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A number of factors influence the probability of obtaining a cure (Table 1) . Tumor diameter correlates with subclinical extension and the likelihood of recurrence [38–40] . Location in high-risk areas for recurrence, especially the nose and periorificial areas on the head and neck, is also an important risk factor (Table 1) . BCC subtype also influences prognosis. BCCs are a heterogeneous group of tumors and a number of subtypes have been identified [41] . Nodular and superficial BCCs comprise up to 70% of lesions and generally have favorable outcomes. Less common forms include the infiltrating, micronodular, morpheaform and basosquamous types. Although each comprises less than 5% of BCCs, these histological subtypes are clinically important because their growth patterns can make them more aggressive or increase their subclinical extension [42,43] . Basosquamous carcinoma may be associated with increased metastatic potential [44–46] . Some tumors contain more than one subtype [47] ; these should be treated according to the component with the poorest prognosis [26] . Perineural infiltration occurs in about 3% of BCCs [48] and is associated with greater subclinical extension and a higher probability of recurrence [49] . Appropriate imaging can detect advanced perineural spread and indicates the need for more aggressive therapy, including adjuvant radiotherapy, when appropriate [50] . Definition of locally advanced BCC inappropriate for surgery or radiotherapy
The 7th edition of the American Joint Committee on Cancer (AJCC) has designated the TNM Staging Classification to stage both BCC and squamous cell carcinoma (SCC) [51,52] . We will focus on the characteristics of the primary tumor (T), because nearly all BCCs grow and spread contiguously, and lymph node involvement (N) and metastasis (M) are rare events in BCC (Table 2) . Tumors are classified as N0 when lymph node involvement is absent and
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Table 1. Risk factors for recurrence†. Clinical
Histological
Location
Low risk: trunk and limbs Intermediate risk: forehead, cheek, chin, scalp and neck High risk: nose and periorificial areas on the head and neck
Size (largest tumor diameter) Clinical aspect Disease status
>1 cm for high-risk location >2 cm for low- or intermediate-risk location Ill-defined lesions or morpheaform subtypes Recurrent
Aggressive subtype‡: – Morpheaform – Infiltrating – Basosquamous – Multifocal
Level of evidence 3 (i.e., based on case–control studies). When several subtypes are associated, global prognosis depends on the component with the poorest prognosis. Adapted with permission from [26]. † ‡
N1 to N3 depending on the degree of spread to regional lymph nodes; M0 or M1 are used to indicate the absence or presence of distant metastasis. We propose the pathway presented in Box 1 for establishing whether laBCC is inappropriate for surgery or radiotherapy. T1 noneyelid tumors can generally be treated effectively with local (surgical or medical) therapy, while surgery is often inappropriate for T3 and T4 tumors. T2 noneyelid tumors should be examined on an individual basis, and we propose that they be subclassified into surgically excisable (T2a) and candidates for radiotherapy (T2b) based on the feasibility of obtaining clear surgical margins. This decision should consider tumor size and histological subtype as a function of location, as well as the amount of reconstructive surgery required and the presence of contraindications to radiotherapy. Eyelid tumors have a separate classification scheme according to the AJCC TNM staging classification (Table 3) . We propose that T1, T2a and T2b eyelid tumors are surgically excisable,
while T3 and T4 eyelid tumors are not ideal candidates for surgery. Tumors classified as T3a should be evaluated on an individual basis. Those T3a tumors that do not invade adjacent ocular or orbital structures (i.e., T3a classification based only on size >20 mm) should be considered for radiotherapy, provided that therapy can be delivered while minimizing irradiation of the eye, optic nerve, lachrymal gland and duct. On the other hand, invasive T3a eyelid tumors, as well as T3b and T4 eyelid tumors that are not appropriate for radical local therapy, should be assessed for systemic therapy with vismodegib. Primary tumors
We suggest that T1 and T2a primary BCCs meeting criteria for operability should undergo surgical excision with predetermined margins appropriate for the tumor size, location and histological subtype. If such margins are not achievable, the tumor should be excised with examination of surgical margins and/or the case should be discussed with a radiation oncologist
Table 2. American Joint Committee on Cancer TNM staging classification for cutaneous squamous cell carcinoma and other cutaneous carcinomas. T
Primary tumor in noneyelid carcinoma
Tx T0 Tis T1 T2 T3 T4
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor ≤2 cm in greatest dimension with 2 cm in greatest dimension or tumor any size with ≥2 high-risk features† Tumor with invasion of maxilla, mandible, orbit or temporal bone Tumor with invasion of skeleton (axial or appendicular) or perineural invasion of skull base
Depth/invasion: greater than 2-mm-thickness Clark level ≥IV perinerual invasion. Anatomic location: primary site ear primary site on nonhair-bearing lip. Differentiation: poorly differentiated or undifferentiated. † High-risk features for primary tumor staging. Reproduced with permission from [51].
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Review Peris, Licitra, Ascierto et al. Box 1. Path for determining suitability for therapy with surgery or radiotherapy. We suggest the following path: ●● Carefully measure the tumor ●● Identify histological forms of basal cell carcinoma with high risk of recurrence ●● Estimate the width of surgical margins based on location, size and basal cell carcinoma subtype ●● Estimate the remaining functionality of involved structure (e.g., ear, eye and nose) ●● Consider the possible aesthetic outcome of the intervention ●● Assess the patient’s capacity to support surgery and reconstruction ●● Discuss the expected results and impact on quality of life with the patient; compare this with patient expectations ●● If surgery is not feasible, consider possible alternatives (e.g., radiotherapy) ●● If local therapy is not feasible, consider systemic therapy with vismodegib
to determine if radiotherapy is appropriate. T2b, T3 and T4 tumors are not suitable for surgery and should be referred for multidisciplinary consultation. Those not amenable to radiotherapy are candidates for systemic therapy with vismodegib. Persistent tumors
Persistent BCC lesions meeting criteria for operability undergo surgical re-excision as soon as possible after detection. Re-excision should be performed using standard or staged surgical procedures with appropriately wide margins. Observation alone should not be used because of the known recurrence rate, the poor prognosis of recurrent disease and the risk that the patient may be lost to follow up. Radiotherapy should be an option for patients without contraindications who are older than 70 years and not able or willing to support further surgery. Recurrent tumors
The reported recurrence rate for BCC after surgical excision ranges from 3.5 to 4.4% [35,53–55] .
Recurrence is more common on the central face, the nose and in the nasolabial folds because of the complex subcutaneous anatomy and proximity to critical structures that may preclude obtaining adequate margins. Aggressive BCC histological subtypes are more frequently associated with recurrence [53] . Recurrent BCCs are associated with a higher risk of further local recurrence [35,56] . Relapsing tumors meeting criteria for operability should undergo surgical excision, provided that adequate margins can be achieved. Margins should be examined with intraoperative histology or staged surgery with delayed closure until clear margins are confirmed. MMS, if available, is particularly useful for complicated local recurrences. After a second recurrence, the feasibility of radiotherapy should be assessed before considering other treatment options, especially for lesions located on the head and neck. BCC lesions that recur after radiotherapy are not amenable to further radiotherapy due to the risk of serious late sequelae. These patients should be evaluated for systemic treatment with vismodegib.
Table 3. American Joint Committee on Cancer TNM staging classification for eyelid carcinoma. T
Primary tumor for eyelid carcinoma
Tx T0 Tis T1 T2a T2b T3a
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor ≤5 mm in greatest dimension; not invading tarsal plate or eyelid margin Tumor >5 mm but 10 mm but 20 mm in greatest dimension or invading adjacent ocular or orbital structures; any T with perineural invasion Complete tumor resection requires enucleation, exenteration or bone resection Tumor is not resectable because of extensive invasion of ocular, orbital, craniofacial structures or brain
T3b T4
Reproduced with permission from [52].
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Box 2. Summary of criteria for locally advanced basal cell carcinoma not appropriate for surgery or radiotherapy. Patients with the following conditions are candidates for systemic therapy with vismodegib: ●● Noneyelid tumors: ●● T2 or T3 and not amenable to surgery and/or radiotherapy; ●● T4 ●● Eyelid tumors: ●● T3 and not amenable to surgery and/or radiotherapy; ●● T3b–T4 ●● Tumors recurrent after radiotherapy ●● Tumors requiring surgery with unacceptable loss of function or disfigurement that are not amenable to radiotherapy ●●Patient-specific factors influencing the
appropriateness of surgery
Although a majority of surgical procedures can be performed under local anesthesia, some procedures may require general anesthesia. Moreover, general anesthesia may be necessary for immobilizing patients with compliance problems, strong tremors or dementia to facilitate radiotherapy or surgery. Advanced age is not an absolute contraindication to surgery; however, some of the physical changes associated with aging may prevent certain patients from undergoing general anesthesia. Patients with American Society of Anesthesiologists’ (ASA) Classification of Physical Health grade ≥4 (i.e., severe systemic disease that is a constant threat to life) should not undergo surgery with general anesthesia [57] . Patients with an ASA classification of 3 (i.e., severe systemic disease) should be carefully assessed before deciding, especially in case of major comorbidities, and this decision should follow general practice recommendations [29] . Surgery should be considered inappropriate when it would cause substantial morbidity, disability or disfiguration. This includes, but is not limited to, the loss of an eye or ear, loss of function of the mouth, irreparable destruction of a major facial feature or loss of an appendage. The general health of the patient and his/her ability to withstand arduous surgery and reconstructive procedures must be considered and the decision should be made with the patient and/or family members after the possible outcomes have been explained and they are informed of the options. Criteria for defining laBCC inappropriate for surgery or radiotherapy are summarized in Box 2. Disclaimer These criteria are based on the best available data and expert clinical experience and are intended
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only as a guide for determining the suitability of locally advanced BCC for surgery or radiotherapy. Ultimately, treatment decisions must consider the severity of the individual patient’s disease and their overall condition, as well as their treatment preferences once informed of the options and likely outcomes. Moreover, ongoing research may reveal new insight into the treatment of BCC. Future perspective Although advanced BCC accounts for approximately 1% of all cases, the high incidence and increasing trend correspond to a substantial and increasing burden in terms of morbidity and mortality. Surgical methods are the gold standard in BCC treatment, with histological confirmation of margins for high-risk lesions. The feasibility of using hedgehog inhibitors in the neoadjuvant setting for inoperable tumors is currently under investigation. Reducing the size of tumors in high-risk locations may allow wider surgical margins to be maintained, while reducing morbidity associated with the procedure and improving cosmetic results. Likewise, when clear margins cannot be obtained, systemic therapy with a hedgehog inhibitor may be useful for treating persistent disease. Not all patients respond to therapy and specific response markers are needed. The mechanisms leading to resistance must be examined thoroughly. An acquired mutation in codon 473 of SMO(D473H) has been identified [58] , and strategies for overcoming this limitation include the development of secondgeneration inhibitors that are efficacious against SMO-D473H. HhAntag has been identified as an SMO inhibitor that is equally effective against wild-type SMO and SMO(D473H). The azole antifungal agent itraconazole is a weak inhibitor of hedgehog signaling that functions through an unknown mechanism [59] .
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Review Peris, Licitra, Ascierto et al. Recently, its use in combination with arsenic trioxide prolonged survival in mice with intracranial tumors expressing SMO(D477G) [60] . Interfering with hedgehog signaling at the level of the GLI transcription factors presents another potential solution. Clinical development of new hedgehog pathway inhibitors will allow switching between inhibitors with different mechanisms of action, which may become a useful strategy for longterm therapy in cases were resistance or intolerance develops. More research is needed to establish the long-term efficacy and safety of vismodegib. Financial & competing interests disclosure This project was supported by an unrestricted grant from Roche. K Peris, L Licitra, PA Ascierto, R Corvò, M Simonacci, F Picciotto, G Gualdi, G Pellacani and A Santoro have received honoraria from Roche for consultant/advisory activities. L Licitra has received honoraria also for a consultant/advisory role from Eisai, BMS, GSK,
Merck Serono, Amgen, Boehringer Ingelheim, Debiopharm, VentiRX and SOBI; received research funds (for her institution) from Eisai, Merck Serono, Amgen and Boehringer Ingelheim; received travel expenses for medical meetings from Merck Serono and Debiopharm. PA Ascierto has received honoraria also for a consultant/ advisory role from BMS, GSK and Novartis and received research funds from BMS. R Corvò has received honoraria also as a consultant for Therabel Gienne and received honoraria from M Serono. A Santoro has participated also on advisory boards for Bayer, Takeda, Daiichi, Arqule, GSK, Novartis, Ariad and received honoraria. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Editorial assistance in the preparation of this manuscript was provided by R Vernell, an independent medical writer, on behalf of Springer Healthcare Communications. This assistance was funded by an unrestricted grant from Roche.
EXECUTIVE SUMMARY Basal cell carcinoma ●●
Basal cell carcinoma (BCC), the most common form of skin cancer, can be locally invasive if neglected, recurrent and/or if an aggressive subtype is involved; in rare cases, it can metastasize.
●●
Most BCCs harbor genetic alterations that inappropriately activate Hedgehog signaling and drive uncontrolled proliferation, making this pathway a therapeutic target.
Targeted therapy with vismodegib ●●
The hedgehog pathway inhibitor vismodegib is approved for adult patients with symptomatic metastatic BCC or locally advanced BCC not appropriate for surgery or radiotherapy;
●●
However, a consensus definition of advanced BCC is currently lacking.
Criteria for defining BCC not amenable to local therapy ●●
Criteria are proposed for defining advanced BCC inappropriate for surgery or radiotherapy; tumor parameters (size,
location, subtype and recurrence status), the patient’s ability to support surgery and reconstruction and the expected outcomes are considered.
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Identifying locally advanced basal cell carcinoma eligible for treatment with vismodegib: an expert panel consensus Ketty Peris*,1, Lisa Licitra2, Paolo A Ascierto3, Renzo Corvò4, Marco Simonacci5, Franco Picciotto6, Giulio Gualdi7, Giovanni Pellacani8 & Armando Santoro9
ABSTRACT Basal cell carcinoma (BCC) is the most common skin cancer worldwide. Most occur on the head and neck, where cosmetic and functional outcomes are critical. BCC can be locally destructive if not diagnosed early and treated appropriately. Surgery is the treatment of choice for the majority of high-risk lesions. Aggressive, recurrent or unresectable tumors can be difficult to manage. Until recently, no approved systemic therapy was available for locally advanced or metastatic BCC inappropriate for surgery or radiotherapy. Vismodegib provides a systemic treatment option. However, a consensus definition of advanced BCC is lacking. A multidisciplinary panel with expertise in oncology, dermatology, dermatologic surgery and radiation oncology proposes a consensus definition based on published evidence and clinical experience. Basal cell carcinoma (BCC) is the most common form of skin cancer worldwide, with an incidence that varies geographically from >1000/100,000 in Australia to 1/100,000 in some African countries, and an increasing trend in many European countries [1] . However, it is difficult to appreciate the scale of the problem because often BCC is not reported in tumor registries. A recent estimate of the BCC incidence in the UK, based on histopathology databases, indicates that the actual number may be twice of that reported in the National Tumor Registry [2] . In the USA, analysis of a private healthcare database with 14 million enrollees revealed an estimated BCC incidence of approximately 560/100,000 in 2010 and an incidence of locally advanced BCC (laBCC) of approximately 8/100,000, corresponding to nearly 30,000 new cases of laBCC [3] . BCCs usually are slow-growing skin tumors that originate from long-lived progenitor cells in the interfollicular epidermis [4] or from hair follicle stem cells [5] . Risk factors for BCC include exposure to ultraviolet (UV) radiation, especially in subjects with fair skin and blue/green eyes, advanced age, prolonged immunosuppression or a personal or family history of skin cancer [6] . Consistent with the role of UV radiation exposure, 80% of BCCs occur on the head or neck [7] . Development of BCC is also associated with several hereditary syndromes including basal cell nevus syndrome, Bazex–Dupré–Christol syndrome, Rombo syndrome, Oley syndrome and xeroderma pigmentosum [8] .
KEYWORDS
• basal cell carcinoma • locally advanced basal cell carcinoma • therapy • vismodegib
Department of Dermatology, Catholic University of Rome, Rome, Italy Head & Neck Medical Oncology Unit, Fondazione IRCCS Istituto Tumori, Milan, Italy 3 Melanoma Cancer Immunotherapy & Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione ‘G Pascale’, Naples, Italy 4 Department of Radiation Oncology, IRCCs San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, University of Genoa – DISSAL, Genoa, Italy 5 Dermatological Unit, Macerata Hospital, Macerata, Italy 6 Section of Dermatologic Surgery, Department of Oncology & Haematology. AOU Città della Salute e della Scienza, Turin, Italy 7 Department of Dermatology, Spedali Civili Brescia, Italy 8 Department of Dermatology, University of Modena & Reggio Emilia, Modena, Italy 9 Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS, Rozzano (Milan), Italy *Author for correspondence: Tel.: +39 06 30 15 4227/4221; Fax: +39 06 30 16 293; [email protected] 1 2
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Review Peris, Licitra, Ascierto et al. The first-line treatment for BCC is surgical excision, whereas radiotherapy may be indicated when surgery is not appropriate or is contraindicated. Other nonsurgical techniques (e.g., photodynamic therapy and topical therapies) may be useful in certain cases [9] . BCC can be locally invasive if neglected, recurrent and/or an aggressive subtype; in rare cases, it can metastasize [7] . Tumors may progress to the point that surgical excision is no longer possible or would result in unacceptable disfigurement or loss of function (Figures 1–3) . Patients who are not good candidates for surgery may benefit from radiotherapy. However, large or multifocal lesions are not necessarily indications for radiation therapy. Further radiotherapy for lesions recurring after radiotherapy is not advisable due to the potential for acquired radioresistance. Approximately 1% of patients with BCC develop advanced disease [10] . Until recently, no systemic therapy was approved for treatment of advanced BCC, and in the past, patients were treated mainly with cisplatin alone or in combination with other drugs, with limited efficacy and considerable side effects [11] . ●●Vismodegib
Most BCCs harbor genetic alterations that inappropriately activate hedgehog signaling. This pathway is normally controlled by PTCH1,
Figure 1. A basal cell carcinoma on the left temporal-parietal region of an 80-year-old patient. This tumor had recurred multiple times after surgical excision with margin control.
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which inhibits the signaling activity of the smoothened homolog (SMO) and subsequent activation of downstream target genes. Loss of PTCH1 function, or more rarely activating mutations in SMO, drive uncontrolled proliferation in sporadic BCC and in BCC associated with basal cell nevus syndrome [12–14] . Thus, this pathway is an attractive therapeutic target in BCC. Vismodegib is a first-in-class, small molecule inhibitor of SMO that was approved in 2012 in the USA and conditionally approved in the EU for adult patients with symptomatic metastatic BCC or laBCC inappropriate for surgery or radiotherapy. A Phase I trial in 33 patients with inoperable tumors or tumors for which surgery was inappropriate showed responses in 19/33 patients, with a median response duration of 12.8 months [15,16] . The pivotal, nonrandomized Phase II ERIVANCE BCC trial enrolled 104 patients with metastatic BCC or laBCC. Patients with laBCC had inoperable tumors or surgery was inappropriate due to multiple recurrences, low likelihood of cure or high probability of substantial disfigurement. All patients received vismodegib 150 mg once daily until disease progression, intolerable toxicity or withdrawal from the study. Objective response rates (ORR) determined by an independent review were 43% (27/63) for laBCC and 30% (10/33) for metastatic BCC. Complete responses were observed in 13 patients (21%). Median response duration was 7.6 months [17] . These response rates were confirmed in an open-label expanded access study of 119 patients that revealed ORRs of 46.4% in patients with laBCC and 30.8% in patients with metastatic BCC [18] . The study was discontinued upon US FDA approval of vismodegib after a median 5.5 (range: 0.4–19.6) months of treatment. The most common adverse events were similar to those reported in previous studies of vismodegib, and comprised muscle spasms (70.6%), dysgeusia (70.6%), alopecia (58.0%) and diarrhea (25.2%). Most of these were grade 1 or 2. One treatment-related grade 3 adverse event was reported (muscle spasms); two patients discontinued because of drug-related adverse events. Long-term treatment with vismodegib has not been investigated thoroughly, and few patients have been treated for longer than 24 months. Not all patients tolerate therapy, and treatment duration may be limited by intolerable toxicity.
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Basal cell carcinoma eligible for vismodegib This has important implication because vismodegib does not eradicate the disease, and tumors regrow when therapy is stopped [19] . Another common reason for interrupting therapy is disease progression. Resistance to vismodegib has been reported [20] and mechanisms of acquired resistance have been described [21] . Neoadjuvant therapy with vismodegib may provide a bridge to curative therapy [22] . Availability of the first approved systemic therapy for advanced BCC provides a treatment for patients who are no longer candidates for surgery or radiotherapy. A consensus definition of advanced BCC is currently lacking [23] . We propose criteria based on published evidence and clinical experience for defining laBCC inappropriate for surgery or radiotherapy. Methods A nine-member multidisciplinary panel with expertise in oncology, dermatology, dermatologic surgery and radiation oncology met to present and discuss available evidence and their clinical and/or research experience with advanced BCC. A draft consensus document defining laBCC not amenable to local therapy emerged. Differences were resolved through discussion and a consensus was defined as the majority position. Subsequent rounds of revision were carried out through electronic mail and the final version was discussed and approved in teleconference. Management of basal cell carcinoma When choosing the most appropriate therapy for BCC, factors including tumor location and size, histological subtype and whether the lesion is recurrent must be considered. Further considerations include the patient’s ability and willingness to tolerate surgery and reconstruction, and suitability for radiotherapy. Currently, surgical excision is recommended as first-line treatment in nearly all cases of BCC [24–29] . The goal of surgery is to obtain a cure by excision with clear lateral and deep surgical margins, while sparing function and achieving a good cosmetic outcome. Most nodular or superficial BCCs occurring outside of high-risk areas can be surgically removed under local anesthesia using 3-4 mm surgical margins with excision down to subcutaneous fat [30] . On the other hand, management of large, infiltrative or recurrent tumors may require extensive resection, sometimes under
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Figure 2. Multiple basal cell carcinomas on the face. (A) A patient with multiple lesions on the face: each of the individual lesions is amenable to surgical removal, but overall, surgery is not indicated. (B) Detail of multifocal lesions that appeared near the surgical scar of an extensive and histologically radical resection. Patient not suitable for radiotherapy due to broad extension.
general anesthesia, followed by arduous reconstructive procedures. In such cases, lateral margins may vary from 5 to 15 mm or more depending on tumor size, location and histological subtype, whereas deep margins are determined by the depth of penetration and nature of the underlying tissue [30] . Postoperative assessment of margins is mandatory and in some high-risk tumors, intraoperative assessment of margins may be indicated. Mohs micrographic surgery (MMS) and its variants (e.g., ‘slow’ Mohs surgery) allow systematic assessment of lateral and deep margins, with further staged excision of involved areas as required. MMS generally provides cure rates of 97–99% for primary BCC and 92–95% for previously treated tumors [31–33] . Randomized clinical trials comparing surgical excision and MMS reveal that both techniques provide excellent control rates for primary tumors [34,35] . MMS had better 5-year recurrence rates when treating recurrent tumors. Moreover, MMS has the advantage of sparing healthy tissue, which is important when treating lesions in cosmetically and functionally sensitive areas. MMS may be particularly suitable for recurrent periorificial BCC. BCCs are generally radiosensitive cancers [36] . Short treatment courses with superficial X-rays, γ-rays or an electron beam with addition of a 5–10 mm margin around the tumor results in high cure rates, especially for early lesions [37] . Radiotherapy may be used with radical, adjuvant (surgery with close or involved margins) or palliative intent, but is not indicated
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Review Peris, Licitra, Ascierto et al. patients hypersensitive to radiation, such as those with basal cell nevus syndrome. Radiotherapy is contraindicated also for tumors involving cartilage or bone, due to the risk of chondro- or osteoradionecrosis, and should be used with caution in patients with connective tissue diseases such as scleroderma or lupus erythematosus. ●●Tumor-specific factors influencing
appropriateness of surgery
Figure 3. Basal cell carcinoma recurrence after three successive surgical excisions and one cycle of radiotherapy. There is infiltration of the galea and periosteum.
for multifocal BCC or extensive tumors with bleeding or infected areas. Radiotherapy is particularly useful for inoperable BCC involving the tip of the nose, lip commissure, inner canthus of the eye or eyelid [30] . Tumors near radiosensitive organs at risk of severe acute or late toxicities require treatment with radiotherapy equipment capable of providing a steep dose gradient between the BCC and surrounding healthy tissue. Thus, referral may be indicated if such equipment and expertise are not available. Potential side effects occurring at the irradiated site include skin atrophy, alopecia and telangiectasia. Because of the risk of secondary tumors, radiotherapy is indicated for older patients (>70 years), and is contraindicated in
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A number of factors influence the probability of obtaining a cure (Table 1) . Tumor diameter correlates with subclinical extension and the likelihood of recurrence [38–40] . Location in high-risk areas for recurrence, especially the nose and periorificial areas on the head and neck, is also an important risk factor (Table 1) . BCC subtype also influences prognosis. BCCs are a heterogeneous group of tumors and a number of subtypes have been identified [41] . Nodular and superficial BCCs comprise up to 70% of lesions and generally have favorable outcomes. Less common forms include the infiltrating, micronodular, morpheaform and basosquamous types. Although each comprises less than 5% of BCCs, these histological subtypes are clinically important because their growth patterns can make them more aggressive or increase their subclinical extension [42,43] . Basosquamous carcinoma may be associated with increased metastatic potential [44–46] . Some tumors contain more than one subtype [47] ; these should be treated according to the component with the poorest prognosis [26] . Perineural infiltration occurs in about 3% of BCCs [48] and is associated with greater subclinical extension and a higher probability of recurrence [49] . Appropriate imaging can detect advanced perineural spread and indicates the need for more aggressive therapy, including adjuvant radiotherapy, when appropriate [50] . Definition of locally advanced BCC inappropriate for surgery or radiotherapy
The 7th edition of the American Joint Committee on Cancer (AJCC) has designated the TNM Staging Classification to stage both BCC and squamous cell carcinoma (SCC) [51,52] . We will focus on the characteristics of the primary tumor (T), because nearly all BCCs grow and spread contiguously, and lymph node involvement (N) and metastasis (M) are rare events in BCC (Table 2) . Tumors are classified as N0 when lymph node involvement is absent and
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Table 1. Risk factors for recurrence†. Clinical
Histological
Location
Low risk: trunk and limbs Intermediate risk: forehead, cheek, chin, scalp and neck High risk: nose and periorificial areas on the head and neck
Size (largest tumor diameter) Clinical aspect Disease status
>1 cm for high-risk location >2 cm for low- or intermediate-risk location Ill-defined lesions or morpheaform subtypes Recurrent
Aggressive subtype‡: – Morpheaform – Infiltrating – Basosquamous – Multifocal
Level of evidence 3 (i.e., based on case–control studies). When several subtypes are associated, global prognosis depends on the component with the poorest prognosis. Adapted with permission from [26]. † ‡
N1 to N3 depending on the degree of spread to regional lymph nodes; M0 or M1 are used to indicate the absence or presence of distant metastasis. We propose the pathway presented in Box 1 for establishing whether laBCC is inappropriate for surgery or radiotherapy. T1 noneyelid tumors can generally be treated effectively with local (surgical or medical) therapy, while surgery is often inappropriate for T3 and T4 tumors. T2 noneyelid tumors should be examined on an individual basis, and we propose that they be subclassified into surgically excisable (T2a) and candidates for radiotherapy (T2b) based on the feasibility of obtaining clear surgical margins. This decision should consider tumor size and histological subtype as a function of location, as well as the amount of reconstructive surgery required and the presence of contraindications to radiotherapy. Eyelid tumors have a separate classification scheme according to the AJCC TNM staging classification (Table 3) . We propose that T1, T2a and T2b eyelid tumors are surgically excisable,
while T3 and T4 eyelid tumors are not ideal candidates for surgery. Tumors classified as T3a should be evaluated on an individual basis. Those T3a tumors that do not invade adjacent ocular or orbital structures (i.e., T3a classification based only on size >20 mm) should be considered for radiotherapy, provided that therapy can be delivered while minimizing irradiation of the eye, optic nerve, lachrymal gland and duct. On the other hand, invasive T3a eyelid tumors, as well as T3b and T4 eyelid tumors that are not appropriate for radical local therapy, should be assessed for systemic therapy with vismodegib. Primary tumors
We suggest that T1 and T2a primary BCCs meeting criteria for operability should undergo surgical excision with predetermined margins appropriate for the tumor size, location and histological subtype. If such margins are not achievable, the tumor should be excised with examination of surgical margins and/or the case should be discussed with a radiation oncologist
Table 2. American Joint Committee on Cancer TNM staging classification for cutaneous squamous cell carcinoma and other cutaneous carcinomas. T
Primary tumor in noneyelid carcinoma
Tx T0 Tis T1 T2 T3 T4
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor ≤2 cm in greatest dimension with 2 cm in greatest dimension or tumor any size with ≥2 high-risk features† Tumor with invasion of maxilla, mandible, orbit or temporal bone Tumor with invasion of skeleton (axial or appendicular) or perineural invasion of skull base
Depth/invasion: greater than 2-mm-thickness Clark level ≥IV perinerual invasion. Anatomic location: primary site ear primary site on nonhair-bearing lip. Differentiation: poorly differentiated or undifferentiated. † High-risk features for primary tumor staging. Reproduced with permission from [51].
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Review Peris, Licitra, Ascierto et al. Box 1. Path for determining suitability for therapy with surgery or radiotherapy. We suggest the following path: ●● Carefully measure the tumor ●● Identify histological forms of basal cell carcinoma with high risk of recurrence ●● Estimate the width of surgical margins based on location, size and basal cell carcinoma subtype ●● Estimate the remaining functionality of involved structure (e.g., ear, eye and nose) ●● Consider the possible aesthetic outcome of the intervention ●● Assess the patient’s capacity to support surgery and reconstruction ●● Discuss the expected results and impact on quality of life with the patient; compare this with patient expectations ●● If surgery is not feasible, consider possible alternatives (e.g., radiotherapy) ●● If local therapy is not feasible, consider systemic therapy with vismodegib
to determine if radiotherapy is appropriate. T2b, T3 and T4 tumors are not suitable for surgery and should be referred for multidisciplinary consultation. Those not amenable to radiotherapy are candidates for systemic therapy with vismodegib. Persistent tumors
Persistent BCC lesions meeting criteria for operability undergo surgical re-excision as soon as possible after detection. Re-excision should be performed using standard or staged surgical procedures with appropriately wide margins. Observation alone should not be used because of the known recurrence rate, the poor prognosis of recurrent disease and the risk that the patient may be lost to follow up. Radiotherapy should be an option for patients without contraindications who are older than 70 years and not able or willing to support further surgery. Recurrent tumors
The reported recurrence rate for BCC after surgical excision ranges from 3.5 to 4.4% [35,53–55] .
Recurrence is more common on the central face, the nose and in the nasolabial folds because of the complex subcutaneous anatomy and proximity to critical structures that may preclude obtaining adequate margins. Aggressive BCC histological subtypes are more frequently associated with recurrence [53] . Recurrent BCCs are associated with a higher risk of further local recurrence [35,56] . Relapsing tumors meeting criteria for operability should undergo surgical excision, provided that adequate margins can be achieved. Margins should be examined with intraoperative histology or staged surgery with delayed closure until clear margins are confirmed. MMS, if available, is particularly useful for complicated local recurrences. After a second recurrence, the feasibility of radiotherapy should be assessed before considering other treatment options, especially for lesions located on the head and neck. BCC lesions that recur after radiotherapy are not amenable to further radiotherapy due to the risk of serious late sequelae. These patients should be evaluated for systemic treatment with vismodegib.
Table 3. American Joint Committee on Cancer TNM staging classification for eyelid carcinoma. T
Primary tumor for eyelid carcinoma
Tx T0 Tis T1 T2a T2b T3a
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor ≤5 mm in greatest dimension; not invading tarsal plate or eyelid margin Tumor >5 mm but 10 mm but 20 mm in greatest dimension or invading adjacent ocular or orbital structures; any T with perineural invasion Complete tumor resection requires enucleation, exenteration or bone resection Tumor is not resectable because of extensive invasion of ocular, orbital, craniofacial structures or brain
T3b T4
Reproduced with permission from [52].
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Box 2. Summary of criteria for locally advanced basal cell carcinoma not appropriate for surgery or radiotherapy. Patients with the following conditions are candidates for systemic therapy with vismodegib: ●● Noneyelid tumors: ●● T2 or T3 and not amenable to surgery and/or radiotherapy; ●● T4 ●● Eyelid tumors: ●● T3 and not amenable to surgery and/or radiotherapy; ●● T3b–T4 ●● Tumors recurrent after radiotherapy ●● Tumors requiring surgery with unacceptable loss of function or disfigurement that are not amenable to radiotherapy ●●Patient-specific factors influencing the
appropriateness of surgery
Although a majority of surgical procedures can be performed under local anesthesia, some procedures may require general anesthesia. Moreover, general anesthesia may be necessary for immobilizing patients with compliance problems, strong tremors or dementia to facilitate radiotherapy or surgery. Advanced age is not an absolute contraindication to surgery; however, some of the physical changes associated with aging may prevent certain patients from undergoing general anesthesia. Patients with American Society of Anesthesiologists’ (ASA) Classification of Physical Health grade ≥4 (i.e., severe systemic disease that is a constant threat to life) should not undergo surgery with general anesthesia [57] . Patients with an ASA classification of 3 (i.e., severe systemic disease) should be carefully assessed before deciding, especially in case of major comorbidities, and this decision should follow general practice recommendations [29] . Surgery should be considered inappropriate when it would cause substantial morbidity, disability or disfiguration. This includes, but is not limited to, the loss of an eye or ear, loss of function of the mouth, irreparable destruction of a major facial feature or loss of an appendage. The general health of the patient and his/her ability to withstand arduous surgery and reconstructive procedures must be considered and the decision should be made with the patient and/or family members after the possible outcomes have been explained and they are informed of the options. Criteria for defining laBCC inappropriate for surgery or radiotherapy are summarized in Box 2. Disclaimer These criteria are based on the best available data and expert clinical experience and are intended
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only as a guide for determining the suitability of locally advanced BCC for surgery or radiotherapy. Ultimately, treatment decisions must consider the severity of the individual patient’s disease and their overall condition, as well as their treatment preferences once informed of the options and likely outcomes. Moreover, ongoing research may reveal new insight into the treatment of BCC. Future perspective Although advanced BCC accounts for approximately 1% of all cases, the high incidence and increasing trend correspond to a substantial and increasing burden in terms of morbidity and mortality. Surgical methods are the gold standard in BCC treatment, with histological confirmation of margins for high-risk lesions. The feasibility of using hedgehog inhibitors in the neoadjuvant setting for inoperable tumors is currently under investigation. Reducing the size of tumors in high-risk locations may allow wider surgical margins to be maintained, while reducing morbidity associated with the procedure and improving cosmetic results. Likewise, when clear margins cannot be obtained, systemic therapy with a hedgehog inhibitor may be useful for treating persistent disease. Not all patients respond to therapy and specific response markers are needed. The mechanisms leading to resistance must be examined thoroughly. An acquired mutation in codon 473 of SMO(D473H) has been identified [58] , and strategies for overcoming this limitation include the development of secondgeneration inhibitors that are efficacious against SMO-D473H. HhAntag has been identified as an SMO inhibitor that is equally effective against wild-type SMO and SMO(D473H). The azole antifungal agent itraconazole is a weak inhibitor of hedgehog signaling that functions through an unknown mechanism [59] .
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Review Peris, Licitra, Ascierto et al. Recently, its use in combination with arsenic trioxide prolonged survival in mice with intracranial tumors expressing SMO(D477G) [60] . Interfering with hedgehog signaling at the level of the GLI transcription factors presents another potential solution. Clinical development of new hedgehog pathway inhibitors will allow switching between inhibitors with different mechanisms of action, which may become a useful strategy for longterm therapy in cases were resistance or intolerance develops. More research is needed to establish the long-term efficacy and safety of vismodegib. Financial & competing interests disclosure This project was supported by an unrestricted grant from Roche. K Peris, L Licitra, PA Ascierto, R Corvò, M Simonacci, F Picciotto, G Gualdi, G Pellacani and A Santoro have received honoraria from Roche for consultant/advisory activities. L Licitra has received honoraria also for a consultant/advisory role from Eisai, BMS, GSK,
Merck Serono, Amgen, Boehringer Ingelheim, Debiopharm, VentiRX and SOBI; received research funds (for her institution) from Eisai, Merck Serono, Amgen and Boehringer Ingelheim; received travel expenses for medical meetings from Merck Serono and Debiopharm. PA Ascierto has received honoraria also for a consultant/ advisory role from BMS, GSK and Novartis and received research funds from BMS. R Corvò has received honoraria also as a consultant for Therabel Gienne and received honoraria from M Serono. A Santoro has participated also on advisory boards for Bayer, Takeda, Daiichi, Arqule, GSK, Novartis, Ariad and received honoraria. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Editorial assistance in the preparation of this manuscript was provided by R Vernell, an independent medical writer, on behalf of Springer Healthcare Communications. This assistance was funded by an unrestricted grant from Roche.
EXECUTIVE SUMMARY Basal cell carcinoma ●●
Basal cell carcinoma (BCC), the most common form of skin cancer, can be locally invasive if neglected, recurrent and/or if an aggressive subtype is involved; in rare cases, it can metastasize.
●●
Most BCCs harbor genetic alterations that inappropriately activate Hedgehog signaling and drive uncontrolled proliferation, making this pathway a therapeutic target.
Targeted therapy with vismodegib ●●
The hedgehog pathway inhibitor vismodegib is approved for adult patients with symptomatic metastatic BCC or locally advanced BCC not appropriate for surgery or radiotherapy;
●●
However, a consensus definition of advanced BCC is currently lacking.
Criteria for defining BCC not amenable to local therapy ●●
Criteria are proposed for defining advanced BCC inappropriate for surgery or radiotherapy; tumor parameters (size,
location, subtype and recurrence status), the patient’s ability to support surgery and reconstruction and the expected outcomes are considered.
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