Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Advanced Basal Cell Carcinoma: Epidemiology and Therapeutic Innovations

Advanced Basal Cell Carcinoma: Epidemiology and Therapeutic Innovations Curr Derm Rep (2014) 3:40–45 DOI 10.1007/s13671-014-0069-y EPIDEMIOLOGY (A ARMSTRONG, SECTION EDITOR) Advanced Basal Cell Carcinoma: Epidemiology and Therapeutic Innovations Shalini V.Mohan & Anne Lynn S. Chang Published online: 9 February 2014 The Author(s) 2014. This article is published with open access at Springerlink.com Abstract Advanced basal cell carcinomas are a subset of pathway inhibitors represents one of the greatest triumphs of basal cell carcinomas that can be difficult to treat either due translational medicine, bridging basic science of a conserved to their local invasiveness, proximity to vital structures, or developmental pathway with clinical application in patients metastasis. The incidence of all basal cell carcinoma is in- with difficult-to-treat skin cancers [1, 2, 3, 4, 5]. In the coming creasing in the United States, although it is not known whether years, the number of agents in this drug class is expected to advanced basal cell carcinomas (aBCCs) are also increasing. increase. These drugs will be a powerful tool to complement, Recently, highly targeted therapy based on knowledge of the or in some cases substitute, for traditional treatment modalities basal cell carcinoma pathogenesis has become available either for aBCCS, such as excision or radiotherapy. commercially or through human clinical trials. These orally available drugs inhibit the Hedgehog signaling pathway, and lead to advanced basal cell carcinoma shrinkage that can Epidemiology enable preservation of adjacent vital organs. In this review, we outline the role of Hedgehog pathway inhibitors as well as BCC comprises the majority of non-melanoma skin cancers other treatment modalities such as excision, radiotherapy and (NMSCs) and is more common than all other human malig- more traditional chemotherapy in treating advanced basal cell nancies combined. Several lines of evidence suggest that the carcinomas. We also highlight current gaps in knowledge worldwide incidence of BCCs is increasing. In the United regarding the use and side effects of this targeted therapy. States, the diagnosis and treatment of NMSCs has increased dramatically with a growth rate of 77 % over the past two Keywords Basal cell carcinoma Advanced basal cell decades. The fastest growing group is in women under the age . . carcinoma Metastatic basal cell carcinoma Smoothened of 40 years [6, 7]. In other countries such as Singapore where . . . inhibitors Hedgehog pathway inhibitors Vismodegib incidence of BCCs is monitored, the rate of BCCs has been . . Targeted therapy Basal cell nevus syndrome Gorlin’s rising over the past several decades as well [8]. Overall, the syndrome reasons for this dramatic growth have been postulated to include the aging population, changes in sun exposure habits, environmental changes, migration patterns, and to a Introduction lesser extent, increased prevalence of immunosuppressant use [9, 10]. The recent introduction of targeted therapy for advanced basal More than 2.8 million new cases of BCC are diagnosed cell carcinomas (aBCCs) in the form of Hedgehog signaling each year in the United States alone, and are estimated to result in over 3,000 deaths [1]. Fortunately, BCCs are usually diagnosed early and treated [11]. Nevertheless, a recent large, S. V. Mohan A. L. S. Chang (*) retrospective analysis from a major academic center reported Department of Dermatology, Stanford University School of 5-year recurrence rates at 2–3%[12]. Given the high inci- Medicine, 450 Broadway St, MC 5334, Pavilion C, 2nd floor, dence of BCCs, this recurrence rate results in a large number Redwood City, CA 94063, USA e-mail: alschang@stanford.edu of BCCs that are not cured by surgical excision. Furthermore, BCCs that are extensive and infiltrate structures below the S. V. Mohan skin or abut vital structures such as the brain or eyes may be e-mail: shalinim@stanford.edu Curr Derm Rep (2014) 3:40–45 41 difficult to surgically clear without significant morbidity. Psychosocial burdens from aBCC disease include depression, Many of these may become locally advanced or metastasize. anxiety, social isolation, depleted financial resources from BCCs that metastasize to either local or distant lymph nodes treatments, inability to find or maintain employment or inabil- or distant organs would best be addressed through systemic ity to provide for or care for dependent family members. Even therapy. Together, these locally advanced or metastatic BCCs patients whose disease is stable or successfully treated can comprise a disease group termed “advanced BCCs” (aBCCs). have significant limitation in functional ability due to scarring, While accurate estimates of the incidence of aBCCs are disfigurement, and/or chronic pain. difficult to obtain, in part due to the lack of widespread use of Life expectancy in aBCC patients also contributes to the a staging system by dermatologists and lack of uniform economic impact of this disease. Historically, reports of sur- reporting requirements for NMSCs, aBCCs are thought to vival after diagnosis of distant metastasis in BCC patients represent roughly 1–10 % of all BCCs, with metastatic BCCs were grim, estimated at 8–14 months [20]. A more recent accounting for 0.0028–0.5 % [13–15]. From our clinical ex- retrospective case series from 1997–2011 suggested markedly perience, patients presenting with aBCCs appear to fall into improved survival in patients followed at a tertiary care center, two categories, (1) those who present with aBCC due to delay with median survival time of 7 years [13]. Future analysis will in accessing medical attention; or (2) those who have BCCs be needed to identify factors that contribute to survival time, that are intrinsically aggressive and are refractory or recur after and the financial cost of any treatments associated with sur- treatment. vival prolongation. Economic, Physical and Psychosocial Impact of Advanced Therapeutic Innovation of Advanced BCC Treatment BCCs Historically, treatment options available to patient with NMSCs including BCCs account for 4.5 % of Medicare aBCCs were not necessarily based on an understanding of cancer expenditures, making it the fifth most costly cancer to the molecular characteristics of BCC pathogenesis. Treatment treat [16, 17]. From 2005 to 2008, NMSCs accounted for $2.9 options included surgery, radiation, and traditional chemother- billion in average annual expenditures on cancer conditions apies such as cisplatin-based treatment, but without systematic among adults in the U.S. While aBCCs are uncommon, their trials to follow for efficacy and safety, in part due to the rarity size and location may require excision in the operating room and heterogeneity of the condition (Table 1). In essence, there with specialized surgical teams and postoperative hospital was no clearly established or superior treatment modality for stays, likely leading to far greater medical costs than operable aBCCs. In the 1990s, the connection between aberrations of the BCCs that can be managed in the office setting. When non- surgical modalities are utilized in aBCCs, such as radiation or Hedgehog signaling pathway and BCCs in mice was made chemotherapy, the cost of treating aBCCs rises dramatically, [21� ]. Around the same time, multiple studies connected this although there are no studies to date that have formally quan- pathway in humans with both sporadic BCCs and an autosomal titated this. Therapeutic innovations such as Hedgehog path- dominant genetic syndrome predisposing to multiple BCCs, way inhibitors may improve quality of life and extend the basal cell nevus syndrome (BCNS) or Gorlin-Goltz syndrome length of productive lifespan in some patients; however, this [22]. The majority of mutations in sporadic BCCs and BCNS treatment has a significant financial cost, as a one-month patients occur in PTCH1 [23, 24], a protein that inhibits supply of vismodegib currently exceeds $7,500. Patients Smoothened. BCNS patients experience early onset and nu- who respond to the drug and tolerate side effects may be on merous BCCs, due to loss-of-heterozygosity in the PTCH1 this drug indefinitely, as currently there is insufficient data as gene. The second most common mutation in sporadic BCCs to when this drug might be discontinued, heightening long- and BCNS patients are gain-of-function mutations of the term costs. Smoothened gene [25, 26]. Loss of PTCH1 results in the lack Exploratory studies into the physical and psychosocial of Smoothened inhibition, leading to increases in GLI1 levels, impact of advanced BCCs are underway; however, the disease changes in transcription, and subsequent tumorigenesis. Gain- can be challenging to characterize, in part due to variable of-function Smoothened mutations also leads to increased GLI1 progression and rarity of the disease [18, 19]. Anecdotal levels and tumorigenesis [27]. A simplified schematic of the evidence from our clinical experience suggests that aBCC Hedgehog (Hh) pathway is presented in Fig. 1a. patients are subject to significant physical and psychological The story of how the first inhibitor of the Hh pathway, burden. Physical burdens including pain, blood loss with cyclopamine, was discovered is one of the most fascinating in anemia and fatigue, infection risk with open wounds, limita- biomedicine. In the 1960s, pregnant ewes ingesting the Cali- tions in movement or function due to location of aBCCs and fornia corn lily were found to produce one-eyed offspring, or side effects of surgery, radiation or chemotherapy. extreme holoprosencephaly [28]. In the 1970s, the active �� 42 Curr Derm Rep (2014) 3:40–45 agent inducing these changes, cyclopamine, was isolated and its structural formula identified. Subsequent studies in the 1990s in chick embryos demonstrated cyclopamine’s ability to induce holoprosencephaly and to bind the transmembrane protein, Smoothened [29]. Subsequently, a number of ana- logues were developed by modifications to cyclopamine to improve solubility, and oral bioavailability. Collectively, these analogues are called Smoothened inhibitors (SIs), due to their targeting of the Smoothened protein (Fig. 1b). Multiple orally available SIs are currently in human clinical trials against BCCs. The first and only U.S. Food and Drug Administration (FDA) approved SI for aBCCs to date is vismodegib, which became commercially available in 2012. The phase II study with 96 aBCC patients leading to FDA approval demonstrated an independently assessed response rate of 30 % in patients with metastatic BCC and 43 % response rate in locally advanced BCC [30�� ]. A subsequent study of 119 aBCC patients showed similar findings [31]. The availability of vismodegib as highly targeted therapy for aBCCs is one of the greatest success stories in translational medicine. While most SIs in human trials come from the research pipelines of pharmaceutical companies, two existing FDA approved drugs have shown activity against the Hh pathway. These are oral ketoconazole and intravenous arsenic trioxide, both of which are being been tested in mouse models [32� ] and a small number of BCC patients in the research setting, with results currently unpublished. Role of Smoothened inhibitors in Advanced BCC Treatment Along with innovation in therapy come many questions that remain to be answered. First, which aBCC patients are appro- priate for SI treatment? An example clinical decision tree is shown in Fig. 2. However, given the heterogeneity of aBCC patients as far as tumor location and extent and comorbidities, each patient should be considered on a case-by-case basis, in conjunction with multidisciplinary consultation such as med- ical oncology, radiation oncology and surgical specialties. In addition, patients may have differential tolerance for side effects of SIs. As a class, these side effects include muscle spasms, taste disturbance, alopecia, nausea, and fatigue [33]. Anecdotally, muscle spasms have been ameliorated with mus- cle relaxants such as cyclobenzaprine. Nausea and poor oral intake have been addressed with megestrol acetate or dronabinol. SIs are also potent teratogens and two forms of medically reliable birth control should be used in patients (and their partners) with reproductive potential. Patients on SI treatment need to follow closely with their treating physicians to monitor for tumor response and side effects. In addition to regular skin checks, patients may need regular radiologic Table 1 Treatment modalities for advanced basal cell carcinoma (aBCC). Summary of therapeutic options, estimated response and recurrence rate and types of evidence Treatment modality Type of aBCC Response Recurrence Rate Type of Evidence in aBCCs Possible Side Effects or References Rate* Limitations Surgical Excision with margin Locally advanced NA 0.7 % after 4 years No high quality studies comparing excision incomplete removal, scarring, [12, 38–41] evaluation in a study including with Moh’s surgery in locally advanced poor functional or cosmetic high risk facial BCCs alone due to rarity of disease; one outcome lesions randomized study included periocular BCCswithnodifferenceinrecurrence rate in excision (n=5) versus Moh’s(n=6) Moh’s micrographic Locally advanced NA NA but likely less than incomplete removal, skip areas surgery excision Field Therapy Radiotherapy Locally advanced NA 7.5 % after 4 years in Randomized trial comparing radiotherapy Less cosmesis than surgical treatment, [41, 42] study including high with surgery including high risk lesions scarring and dyspigmentation, risk facial lesions risk of secondary cancer Targeted chemotherapy Smoothened inhibitor Locally advanced; 30–43 % 20 % Cohort studies for response rate; small Muscle spasms, dysgeusia, alopecia, [30 , 43, 44] (vismodegib) metastatic retrospective study for recurrence rate fatigue, nausea Non-targeted Cisplatin-based Locally advanced; 71 % - Case series of seven BCC patients with locally Severe nausea and vomiting, diarrhea, [45–49] chemotherapy chemotherapy metastatic advanced disease using cisplatin and alopecia, joint pain, loss of balance, doxorubicin; case reports of cisplatin leading tinnitus, edema, fatigue to complete response in a few metastatic patients * Estimated response rate based on range derived from cited references. Please see original articles for specific details and explanation for basis of estimate Curr Derm Rep (2014) 3:40–45 43 Fig. 1 Simplified schematic of a b Loss of function Gain of function common mutations in the mutation of PTCH1 mutation of SMO Hedgehog signaling pathway Smo inhibitors leading to basal cell carcinoma SHH SHH from pathway activation (a), and therapeutic targets of this SMO PTCH1 SMO PTCH1 BCC BCC pathway (b) Itraconazole Activation of Arsenic trioxide Activation of SMO-GLI SMO-GLI GLI GLI signaling signaling Nucleus Nucleus GLI GLI GLI Target gene GLI Target gene expression expression Tumorigenesis Tumorigenesis imaging to monitor for disease recurrence in cases where the this disease, multicenter registry studies are in progress to aBCC has a deep component or is metastatic to non-skin assess these. organs. If the aBCC is refractory or recurrent, timely interven- Fourth, what is the impact of SI treatment on quality of life tion with other treatment modalities is critical. and psychosocial outcomes? The impact of SI treatment re- Second, can the response rate for aBCCs be increased lates to the efficacy of the drug against the aBCC, as well as when combined with other treatment modalities, such as the tolerability of the side effects. Compared to many other other chemotherapies or radiation treatment? Can recur- forms of chemotherapy, the side effects of SI may be more rence rates be decreased when combined with other treat- tolerable. Alternatively, muscle spasms or other side effects ment modalities? Clinical trials are underway to explore may limit the ability of patients to take the drug in the long these questions. term, and/or maintain a good quality of life despite disease Third, what is the impact of SI treatment on progression stabilization. Patient-based instruments recently have been free survival or overall survival in aBCCs? Given the rarity of developed to better assess these endpoints [18, 19]. Fig. 2 Example treatment algorithm for advanced basal cell carcinoma. Due to disease heterogeneity in advanced basal cell carcinomas, actual treatment depends on tumor location, prior treatments and patient comorbidities 44 Curr Derm Rep (2014) 3:40–45 Open Access This article is distributed under the terms of the Creative Fifth, are there clinical predictors for response to SI treat- Commons Attribution License which permits any use, distribution, and ment? One analysis from an expanded access study in patients reproduction in any medium, provided the original author(s) and the for vismodegib identified prior treatment with systemic ther- source are credited. apy as negatively correlated with laBCC response in 56 pa- tients [34]. There was no association with age, prior radiother- apy or number of sites affected with aBCCs. In this same References study, analysis of 39 metastatic BCCs showed that neither age, prior radiotherapy, prior systemic therapy or number of sites Papers of particular interest, published recently, have been affected with aBCCs were associated with tumor response. highlighted as: Larger prospective studies are underway to assess clinical � Of importance predictors for SI response. �� Of major importance Sixth, are there tumor markers from biopsies to predict 1. Gould A, Missailidis S. Targeting the hedgehog pathway: the response to SI treatment? Given the aggressiveness of development of cyclopamine and the development of anti-cancer many aBCCs, the decision of which treatment modality drugs targeting the hedgehog pathway. Mini Rev Med Chem. to undertake could be life-saving. Current studies are un- 2011;11(3):200–13. derway to assess for mutations, gene expression changes or 2. Sekulic A, Mangold AR, Northfelt DW, LoRusso PM. Advanced basal cell carcinoma of the skin: targeting the hedgehog pathway. protein levels within the Hh signaling pathway [35–37] Curr Opin Oncol. 2013;25(3):218–23. that could correlate with response or lack of response, with 3. Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, the ultimate goal of assisting with clinical decision- Lindgren J, Chang K, et al. Inhibiting the hedgehog pathway in making. As the current cost of SI drugs is quite high, a patients with the basal-cell nevus syndrome. N Engl J Med. 2012;386(23):2180–8. diagnostic test that could indicate the likelihood of re- 4. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas sponse to these drugs may be cost effective. JM, et al. Human homolog of patched, a candidate gene for the Many additional issues remaining to be clarified regarding basal cell nevus syndrome. Science. 1996;272:1668–71. the use of SIs, including: effective management of common 5. Taipale J, Beachy PA. The Hedgehog and Wnt signalling pathways in cancer. Nature. 2001;411(6835):349–54. side effects, long-term side effects such as the potential for 6. "Skin Cancer Foundation." Basal Cell Carcinoma (BCC). Skin secondary cancers, whether there is differential response Cancer Foundation, 2013. Web. 09 June 2013. based on BCC subtype, when SI treatment may be safely 7. Wu TP, Stein JA. Nonmelanoma skin cancer in young women. J discontinued after apparent complete clinical response, and Drugs Dermatol. 2013;12:568–72. 8. Koh D, Wang H, Lee J, Chia KS, Lee HP, Goh CL. Basal cell whether SIs should be used to treat microscopic disease in carcinoma, squamous cell carcinoma and melanoma of the skin: surgical cases where margins are positive. analysis of the Singapore Cancer Registry. Br J Dermatol. 2003;148:1161–6. 9. Weinstock MA, Fisher DE. Indoor ultraviolet tanning: what the data do and do not show regarding risk of melanoma Conclusion and keratinocyte malignancies. J Natl Compr Canc Netw. 2010;8(8):867–72. Advanced BCCs are often difficult to treat and life- 10. Nan H, Kraft P, Hunter DJ, Han J. Genetic variants in pigmentation threatening. SI drugs can be life-saving in many cases, though genes, pigmentary phenotypes, and risk of skin cancer in Caucasians. Int J Cancer. 2009;125(4):909–17. disease progression or recurrence is a major concern that 11. Alam M, Goldberg LH, Silapunt S, Gardner ES, Strom SS, requires regular monitoring through skin examinations and/ Rademaker AW, et al. Delayed treatment and continued growth of or radiologic imaging. Successful management of side effects nonmelanoma skin cancer. J Am Acad Dermatol. 2011;64(5):839– is critical to continued treatment with these drugs. When 12. Chren MM, Linos E, Torres JS, Stuart SE, Parvataeni R, Boscardin aBCCs are refractory, achieve a partial response, or are recur- WJ. Tumor recurrence 5 years after treatment of cutaneous basal rent after SI therapy, other treatment modalities such as radi- cell carcinoma and squamous cell carcinoma. J Invest Dermatol. ation, traditional chemotherapy or surgical excision need to be 2013;133:1188–96. considered for optimum patient outcomes. 13. Danial C, Lingala B, Balise R, Oro AE, Reddy S, Colevas A, Chang AL. Markedly improved overall survival in 10 consecutive meta- static basal cell carcinoma patients. Br J Dermatol 2013: 1365– Compliance with Ethics Guidelines 14. Soleymani AD, Scheinfeld N, Vasil K, Bechtel MA. Metastatic Conflict of Interest SV Mohan declares no conflicts of interest. basal cell carcinoma presenting with unilateral upper extremity ALS Chang has received research support from Genentech, Novartis, edema and lymphatic spread. J Am Acad Dermatol. 2008;59(2 Infinity, and Lilly. suppl 1):s1–3. 15. Moser S, Borm J, Mihic-Probst D, Jacobsen C, Kruse Gujer AL. Metastatic basal cell carcinoma: report of a case and Human and Animal Rights and Informed Consent This article does review of the literature. Oral Surg Oral Med Oral Pathol not contain any studies with human or animal subjects performed by any Oral Radiol 2013 of the authors. Curr Derm Rep (2014) 3:40–45 45 16. Machlin S, Carper K, Kashihara D. Health Care Expenditures for adult patients with solid tumors. Clin Cancer Res. 2013;19(10): Non-Melanoma Skin Cancer among Adults, 2005–2008 (Average 2766–74. Annual). Rockville: Agency for Healthcare Research and Quality; 34. Chang ALS, Soloman JA, Hainsworth JD, Goldberg L, McKenna 2011. E, Day B, Chen DM, Weiss GJ. Expanded access study of advanced 17. Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman basal cell carcinoma patients treated with the Hedgehog pathway SR, Fleischer AB, et al. Incidence estimate of nonmelanoma skin inhibitor, vismodegib. J Am Acad Dermatol. 2013. cancer in the United States, 2006. Arch Dermatol. 2010;146(3): 35. Li ZJ, Mack SC, Mak TH, Angers S, Taylor MD, Hui CC. Evasion 283–87. of p53 and G2/M checkpoints are characteristic of Hh-driven basal 18. Haves AW, Schaffer PR, Carucci JA. The Impact of Inoperable cell carcinoma. Oncogene 2013. Advanced Basal Cell Carcinoma: the Economic, Physical and 36. Heller ER, Gor A, Wang D, Hu Q, Lucchese A, Kanduc D, et al. Psychological Burden of the Disease. J Drugs Dermatol. Molecular signatures of basal cell carcinoma susceptibility and path- 2013;12(10):s151–53. ogenesis: a genomic approach. Int J Oncol. 2013;42(2):583–96. 19. Shingler SL, Garside J, Samanta K, Lear JT, Keohane S, Lloyd AJ. 37. Almquist LM, Karagas MR, Christensen BC, Welsh MM, Perry Utilities for advanced basal cell carcinoma. J Med Econ. AE, Storm CA, et al. The role of TP53 and MDM2 polymorphisms 2013;16(6):777–83. in TP53 mutagenesis and risk of non-melanoma skin cancer. 20. Wysong A, Aasi SZ, Tang JY. Update on metastatic basal cell Carcinogenesis. 2011;32(3):327–30. carcinoma: a summary of published cases from 1981 through 38. Kuijpers DI, Thissen MR, Berretty PJ, Ideler FH, Nelemans PJ, 2011. JAMA Dermatol. 2013;149(5):615–6. Neumann MH. Surgical excision versus curettage plus cryosurgery 21.� Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein EH, Scott MP. in the treatment of basal cell carcinoma. Dermatol Surg. Basal cell carcinomas in mice overexpressing sonic hedgehog. 2007;33(5):579–87. Science. 1997;276(5313):817–21. 39. Smeets NW, Kuijpers DI, Nelemans P, Ostertag JU, Verhaegh ME, 22. Aszterbaum M, Rothman A, Johnson RL, Fisher M, Xie J, Bonifas Krekels GA, et al. Mohs’ micrographic surgery for treatment of JM, et al. Identification of mutations in the human PATCHED gene basal cell carcinoma of the face—results of a retrospective study in sporadic basal cell carcinomas and in patients with the basal cell and review of the literature. Br J Dermatol. 2004;151(1):141–7. nevus syndrome. J Invest Derm. 1998;110(6):885–8. 40. Hamilton JR, Parvataneni R, Stuart SE, Chrem MM. Recurrence 5 23. Wollina U, Tchernev G. Advanced basal cell carcinoma. Wien Med years after treatment of recurrent cutaneous basal cell and squamous Wochenschr 2013 cell carcinoma. JAMA Dermatol. 2013;149(5):616–8. 24. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev 41. Avril MF, Auperin A, Margulis A, Gerbaulet A, Duvillard P, Cancer. 2008;8(10):743–54. Benhamou E, et al. Basal cell carcinoma of the face: surgery or 25. Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, et al. radiotherapy? Results of a randomized study. Br J Cancer. Activating Smoothened mutations in sporadic basal-cell carcinoma. 1997;76(1):100–6. Nature. 1998;391(6662):90–2. 42. Hall VL, Leppard BJ, McGill J, Kesseler ME, White JE, Goodwin 26. Skvara H, Kalthoff F, Meingassner JG, Wolff-Winiski B, Aschauer P. Treatment of basal-cell carcinoma: comparison of radiotherapy H, Kelleher JF, et al. Topical treatment of basal cell carcinomas in and cryotherapy. Clin Radiol. 1986;37(1):33–4. nevoid basal cell carcinoma syndrome with a smoothened inhibitor. 43. Amin SH, Tibes R, Kim JE, Hybarger CP. Hedgehog antagonist J Invest Dermatol. 2011;131(8):1735–44. GDC-0449 is effective in the treatment of advanced basal cell 27. Atwood SX, Chang AS, Oro AE. Hedgehog pathway inhibition and carcinoma. Laryngoscope. 2010;120(12):2456–9. the race against tumor evolution. J Cell Biol. 2012;199(2):193–7. 44. Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, 28. Keeler RF, Binns W. Teratogenic compounds of Veratrum Tibes R, et al. Inhibition of hedgehog pathway in advanced basal- Californicum Coparison of Cyclopian effects of steroidal alkaloids. cell carcinoma. N Engl J Med. 2009;361(12):1164–72. Teratology. 1968;1:5–10. 45. Moeholt K, Aagaard H, Pfeiffer P, Hansen O. Platinum-based 29. Chen JK, Taipale J, Cooper MK, Beachy PA. Inhibition of cytotoxic therapy in basal cell carcinoma a review of the literature. Hedgehog signaling by direct binding of cyclopamine to Acta Oncol. 1996;35(6):677–82. Smothened. Gene Dev. 2002;16:2743–48. 46. Guthrie TH, Porubsky ES, Luxenberg MN, Shah KJ, Wurtz KL, 30.�� Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth Watson PR. Cisplatin-based chemotherapy in advanced basal cell JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma and squamous cell carcinoma of the skin: results in 28 carcinoma. N Engl J Med. 2012;366(23):2171–9. aptients including 13 patients receiving multimodality therapy. J 31. Chang AL, Atwood SX, Tartar DM, Oro AE. Surgical excision Clin Oncol. 1990;8(2):342–6. after neoadjuvant therapy with vismodegib for a locally advanced 47. Denic S. Preoperative treatment of advanced skin carcinoma with basal cell carcinoma and resistant basal carcinomas in Gorlin syn- cisplatin and bleomycin. Am J Clin Oncol. 1999;22(1):32–4. drome. JAMA Dermatol. 2013;149(5):639–41. 48. Carneiro BA, Watkin WG, Mehta UK, Brockstein BE. Metastatic 32.� Kim J, Aftab BT, Tang JY, Kim D, Lee AH, Rezaee M, et al. basal cell carcinoma: complete response to chemotherapy and Itraconazole and arsenic trioxide inhibit hedgehog pathway activa- associated pure red cell aplasia. Cancer Invest. 2006;24(4):396– tion and tumor growth associated with acquired resistance to 400. smoothened antagonists. Cancer Cell. 2013;23(1):23–34. 49. Khandekar JD. Complete response of metastatic basal cell carcino- 33. Jimeno A, Weiss GJ, Miller WH, Gettinger S, Eigl BJ, Chang AL, ma to cisplatin chemotherapy: a report of two patients. Arch et al. Phase 1 study of the Hedgehog pathway inhibitor IPI-926 in Dermatol. 1990;126(12):1,660. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Current Dermatology Reports Pubmed Central

Advanced Basal Cell Carcinoma: Epidemiology and Therapeutic Innovations

Current Dermatology Reports , Volume 3 (1) – Feb 9, 2014

Loading next page...
 
/lp/pubmed-central/advanced-basal-cell-carcinoma-epidemiology-and-therapeutic-innovations-34fKfZy0c9

References (52)

Publisher
Pubmed Central
Copyright
© The Author(s) 2014
eISSN
2162-4933
DOI
10.1007/s13671-014-0069-y
Publisher site
See Article on Publisher Site

Abstract

Curr Derm Rep (2014) 3:40–45 DOI 10.1007/s13671-014-0069-y EPIDEMIOLOGY (A ARMSTRONG, SECTION EDITOR) Advanced Basal Cell Carcinoma: Epidemiology and Therapeutic Innovations Shalini V.Mohan & Anne Lynn S. Chang Published online: 9 February 2014 The Author(s) 2014. This article is published with open access at Springerlink.com Abstract Advanced basal cell carcinomas are a subset of pathway inhibitors represents one of the greatest triumphs of basal cell carcinomas that can be difficult to treat either due translational medicine, bridging basic science of a conserved to their local invasiveness, proximity to vital structures, or developmental pathway with clinical application in patients metastasis. The incidence of all basal cell carcinoma is in- with difficult-to-treat skin cancers [1, 2, 3, 4, 5]. In the coming creasing in the United States, although it is not known whether years, the number of agents in this drug class is expected to advanced basal cell carcinomas (aBCCs) are also increasing. increase. These drugs will be a powerful tool to complement, Recently, highly targeted therapy based on knowledge of the or in some cases substitute, for traditional treatment modalities basal cell carcinoma pathogenesis has become available either for aBCCS, such as excision or radiotherapy. commercially or through human clinical trials. These orally available drugs inhibit the Hedgehog signaling pathway, and lead to advanced basal cell carcinoma shrinkage that can Epidemiology enable preservation of adjacent vital organs. In this review, we outline the role of Hedgehog pathway inhibitors as well as BCC comprises the majority of non-melanoma skin cancers other treatment modalities such as excision, radiotherapy and (NMSCs) and is more common than all other human malig- more traditional chemotherapy in treating advanced basal cell nancies combined. Several lines of evidence suggest that the carcinomas. We also highlight current gaps in knowledge worldwide incidence of BCCs is increasing. In the United regarding the use and side effects of this targeted therapy. States, the diagnosis and treatment of NMSCs has increased dramatically with a growth rate of 77 % over the past two Keywords Basal cell carcinoma Advanced basal cell decades. The fastest growing group is in women under the age . . carcinoma Metastatic basal cell carcinoma Smoothened of 40 years [6, 7]. In other countries such as Singapore where . . . inhibitors Hedgehog pathway inhibitors Vismodegib incidence of BCCs is monitored, the rate of BCCs has been . . Targeted therapy Basal cell nevus syndrome Gorlin’s rising over the past several decades as well [8]. Overall, the syndrome reasons for this dramatic growth have been postulated to include the aging population, changes in sun exposure habits, environmental changes, migration patterns, and to a Introduction lesser extent, increased prevalence of immunosuppressant use [9, 10]. The recent introduction of targeted therapy for advanced basal More than 2.8 million new cases of BCC are diagnosed cell carcinomas (aBCCs) in the form of Hedgehog signaling each year in the United States alone, and are estimated to result in over 3,000 deaths [1]. Fortunately, BCCs are usually diagnosed early and treated [11]. Nevertheless, a recent large, S. V. Mohan A. L. S. Chang (*) retrospective analysis from a major academic center reported Department of Dermatology, Stanford University School of 5-year recurrence rates at 2–3%[12]. Given the high inci- Medicine, 450 Broadway St, MC 5334, Pavilion C, 2nd floor, dence of BCCs, this recurrence rate results in a large number Redwood City, CA 94063, USA e-mail: alschang@stanford.edu of BCCs that are not cured by surgical excision. Furthermore, BCCs that are extensive and infiltrate structures below the S. V. Mohan skin or abut vital structures such as the brain or eyes may be e-mail: shalinim@stanford.edu Curr Derm Rep (2014) 3:40–45 41 difficult to surgically clear without significant morbidity. Psychosocial burdens from aBCC disease include depression, Many of these may become locally advanced or metastasize. anxiety, social isolation, depleted financial resources from BCCs that metastasize to either local or distant lymph nodes treatments, inability to find or maintain employment or inabil- or distant organs would best be addressed through systemic ity to provide for or care for dependent family members. Even therapy. Together, these locally advanced or metastatic BCCs patients whose disease is stable or successfully treated can comprise a disease group termed “advanced BCCs” (aBCCs). have significant limitation in functional ability due to scarring, While accurate estimates of the incidence of aBCCs are disfigurement, and/or chronic pain. difficult to obtain, in part due to the lack of widespread use of Life expectancy in aBCC patients also contributes to the a staging system by dermatologists and lack of uniform economic impact of this disease. Historically, reports of sur- reporting requirements for NMSCs, aBCCs are thought to vival after diagnosis of distant metastasis in BCC patients represent roughly 1–10 % of all BCCs, with metastatic BCCs were grim, estimated at 8–14 months [20]. A more recent accounting for 0.0028–0.5 % [13–15]. From our clinical ex- retrospective case series from 1997–2011 suggested markedly perience, patients presenting with aBCCs appear to fall into improved survival in patients followed at a tertiary care center, two categories, (1) those who present with aBCC due to delay with median survival time of 7 years [13]. Future analysis will in accessing medical attention; or (2) those who have BCCs be needed to identify factors that contribute to survival time, that are intrinsically aggressive and are refractory or recur after and the financial cost of any treatments associated with sur- treatment. vival prolongation. Economic, Physical and Psychosocial Impact of Advanced Therapeutic Innovation of Advanced BCC Treatment BCCs Historically, treatment options available to patient with NMSCs including BCCs account for 4.5 % of Medicare aBCCs were not necessarily based on an understanding of cancer expenditures, making it the fifth most costly cancer to the molecular characteristics of BCC pathogenesis. Treatment treat [16, 17]. From 2005 to 2008, NMSCs accounted for $2.9 options included surgery, radiation, and traditional chemother- billion in average annual expenditures on cancer conditions apies such as cisplatin-based treatment, but without systematic among adults in the U.S. While aBCCs are uncommon, their trials to follow for efficacy and safety, in part due to the rarity size and location may require excision in the operating room and heterogeneity of the condition (Table 1). In essence, there with specialized surgical teams and postoperative hospital was no clearly established or superior treatment modality for stays, likely leading to far greater medical costs than operable aBCCs. In the 1990s, the connection between aberrations of the BCCs that can be managed in the office setting. When non- surgical modalities are utilized in aBCCs, such as radiation or Hedgehog signaling pathway and BCCs in mice was made chemotherapy, the cost of treating aBCCs rises dramatically, [21� ]. Around the same time, multiple studies connected this although there are no studies to date that have formally quan- pathway in humans with both sporadic BCCs and an autosomal titated this. Therapeutic innovations such as Hedgehog path- dominant genetic syndrome predisposing to multiple BCCs, way inhibitors may improve quality of life and extend the basal cell nevus syndrome (BCNS) or Gorlin-Goltz syndrome length of productive lifespan in some patients; however, this [22]. The majority of mutations in sporadic BCCs and BCNS treatment has a significant financial cost, as a one-month patients occur in PTCH1 [23, 24], a protein that inhibits supply of vismodegib currently exceeds $7,500. Patients Smoothened. BCNS patients experience early onset and nu- who respond to the drug and tolerate side effects may be on merous BCCs, due to loss-of-heterozygosity in the PTCH1 this drug indefinitely, as currently there is insufficient data as gene. The second most common mutation in sporadic BCCs to when this drug might be discontinued, heightening long- and BCNS patients are gain-of-function mutations of the term costs. Smoothened gene [25, 26]. Loss of PTCH1 results in the lack Exploratory studies into the physical and psychosocial of Smoothened inhibition, leading to increases in GLI1 levels, impact of advanced BCCs are underway; however, the disease changes in transcription, and subsequent tumorigenesis. Gain- can be challenging to characterize, in part due to variable of-function Smoothened mutations also leads to increased GLI1 progression and rarity of the disease [18, 19]. Anecdotal levels and tumorigenesis [27]. A simplified schematic of the evidence from our clinical experience suggests that aBCC Hedgehog (Hh) pathway is presented in Fig. 1a. patients are subject to significant physical and psychological The story of how the first inhibitor of the Hh pathway, burden. Physical burdens including pain, blood loss with cyclopamine, was discovered is one of the most fascinating in anemia and fatigue, infection risk with open wounds, limita- biomedicine. In the 1960s, pregnant ewes ingesting the Cali- tions in movement or function due to location of aBCCs and fornia corn lily were found to produce one-eyed offspring, or side effects of surgery, radiation or chemotherapy. extreme holoprosencephaly [28]. In the 1970s, the active �� 42 Curr Derm Rep (2014) 3:40–45 agent inducing these changes, cyclopamine, was isolated and its structural formula identified. Subsequent studies in the 1990s in chick embryos demonstrated cyclopamine’s ability to induce holoprosencephaly and to bind the transmembrane protein, Smoothened [29]. Subsequently, a number of ana- logues were developed by modifications to cyclopamine to improve solubility, and oral bioavailability. Collectively, these analogues are called Smoothened inhibitors (SIs), due to their targeting of the Smoothened protein (Fig. 1b). Multiple orally available SIs are currently in human clinical trials against BCCs. The first and only U.S. Food and Drug Administration (FDA) approved SI for aBCCs to date is vismodegib, which became commercially available in 2012. The phase II study with 96 aBCC patients leading to FDA approval demonstrated an independently assessed response rate of 30 % in patients with metastatic BCC and 43 % response rate in locally advanced BCC [30�� ]. A subsequent study of 119 aBCC patients showed similar findings [31]. The availability of vismodegib as highly targeted therapy for aBCCs is one of the greatest success stories in translational medicine. While most SIs in human trials come from the research pipelines of pharmaceutical companies, two existing FDA approved drugs have shown activity against the Hh pathway. These are oral ketoconazole and intravenous arsenic trioxide, both of which are being been tested in mouse models [32� ] and a small number of BCC patients in the research setting, with results currently unpublished. Role of Smoothened inhibitors in Advanced BCC Treatment Along with innovation in therapy come many questions that remain to be answered. First, which aBCC patients are appro- priate for SI treatment? An example clinical decision tree is shown in Fig. 2. However, given the heterogeneity of aBCC patients as far as tumor location and extent and comorbidities, each patient should be considered on a case-by-case basis, in conjunction with multidisciplinary consultation such as med- ical oncology, radiation oncology and surgical specialties. In addition, patients may have differential tolerance for side effects of SIs. As a class, these side effects include muscle spasms, taste disturbance, alopecia, nausea, and fatigue [33]. Anecdotally, muscle spasms have been ameliorated with mus- cle relaxants such as cyclobenzaprine. Nausea and poor oral intake have been addressed with megestrol acetate or dronabinol. SIs are also potent teratogens and two forms of medically reliable birth control should be used in patients (and their partners) with reproductive potential. Patients on SI treatment need to follow closely with their treating physicians to monitor for tumor response and side effects. In addition to regular skin checks, patients may need regular radiologic Table 1 Treatment modalities for advanced basal cell carcinoma (aBCC). Summary of therapeutic options, estimated response and recurrence rate and types of evidence Treatment modality Type of aBCC Response Recurrence Rate Type of Evidence in aBCCs Possible Side Effects or References Rate* Limitations Surgical Excision with margin Locally advanced NA 0.7 % after 4 years No high quality studies comparing excision incomplete removal, scarring, [12, 38–41] evaluation in a study including with Moh’s surgery in locally advanced poor functional or cosmetic high risk facial BCCs alone due to rarity of disease; one outcome lesions randomized study included periocular BCCswithnodifferenceinrecurrence rate in excision (n=5) versus Moh’s(n=6) Moh’s micrographic Locally advanced NA NA but likely less than incomplete removal, skip areas surgery excision Field Therapy Radiotherapy Locally advanced NA 7.5 % after 4 years in Randomized trial comparing radiotherapy Less cosmesis than surgical treatment, [41, 42] study including high with surgery including high risk lesions scarring and dyspigmentation, risk facial lesions risk of secondary cancer Targeted chemotherapy Smoothened inhibitor Locally advanced; 30–43 % 20 % Cohort studies for response rate; small Muscle spasms, dysgeusia, alopecia, [30 , 43, 44] (vismodegib) metastatic retrospective study for recurrence rate fatigue, nausea Non-targeted Cisplatin-based Locally advanced; 71 % - Case series of seven BCC patients with locally Severe nausea and vomiting, diarrhea, [45–49] chemotherapy chemotherapy metastatic advanced disease using cisplatin and alopecia, joint pain, loss of balance, doxorubicin; case reports of cisplatin leading tinnitus, edema, fatigue to complete response in a few metastatic patients * Estimated response rate based on range derived from cited references. Please see original articles for specific details and explanation for basis of estimate Curr Derm Rep (2014) 3:40–45 43 Fig. 1 Simplified schematic of a b Loss of function Gain of function common mutations in the mutation of PTCH1 mutation of SMO Hedgehog signaling pathway Smo inhibitors leading to basal cell carcinoma SHH SHH from pathway activation (a), and therapeutic targets of this SMO PTCH1 SMO PTCH1 BCC BCC pathway (b) Itraconazole Activation of Arsenic trioxide Activation of SMO-GLI SMO-GLI GLI GLI signaling signaling Nucleus Nucleus GLI GLI GLI Target gene GLI Target gene expression expression Tumorigenesis Tumorigenesis imaging to monitor for disease recurrence in cases where the this disease, multicenter registry studies are in progress to aBCC has a deep component or is metastatic to non-skin assess these. organs. If the aBCC is refractory or recurrent, timely interven- Fourth, what is the impact of SI treatment on quality of life tion with other treatment modalities is critical. and psychosocial outcomes? The impact of SI treatment re- Second, can the response rate for aBCCs be increased lates to the efficacy of the drug against the aBCC, as well as when combined with other treatment modalities, such as the tolerability of the side effects. Compared to many other other chemotherapies or radiation treatment? Can recur- forms of chemotherapy, the side effects of SI may be more rence rates be decreased when combined with other treat- tolerable. Alternatively, muscle spasms or other side effects ment modalities? Clinical trials are underway to explore may limit the ability of patients to take the drug in the long these questions. term, and/or maintain a good quality of life despite disease Third, what is the impact of SI treatment on progression stabilization. Patient-based instruments recently have been free survival or overall survival in aBCCs? Given the rarity of developed to better assess these endpoints [18, 19]. Fig. 2 Example treatment algorithm for advanced basal cell carcinoma. Due to disease heterogeneity in advanced basal cell carcinomas, actual treatment depends on tumor location, prior treatments and patient comorbidities 44 Curr Derm Rep (2014) 3:40–45 Open Access This article is distributed under the terms of the Creative Fifth, are there clinical predictors for response to SI treat- Commons Attribution License which permits any use, distribution, and ment? One analysis from an expanded access study in patients reproduction in any medium, provided the original author(s) and the for vismodegib identified prior treatment with systemic ther- source are credited. apy as negatively correlated with laBCC response in 56 pa- tients [34]. There was no association with age, prior radiother- apy or number of sites affected with aBCCs. In this same References study, analysis of 39 metastatic BCCs showed that neither age, prior radiotherapy, prior systemic therapy or number of sites Papers of particular interest, published recently, have been affected with aBCCs were associated with tumor response. highlighted as: Larger prospective studies are underway to assess clinical � Of importance predictors for SI response. �� Of major importance Sixth, are there tumor markers from biopsies to predict 1. Gould A, Missailidis S. Targeting the hedgehog pathway: the response to SI treatment? Given the aggressiveness of development of cyclopamine and the development of anti-cancer many aBCCs, the decision of which treatment modality drugs targeting the hedgehog pathway. Mini Rev Med Chem. to undertake could be life-saving. Current studies are un- 2011;11(3):200–13. derway to assess for mutations, gene expression changes or 2. Sekulic A, Mangold AR, Northfelt DW, LoRusso PM. Advanced basal cell carcinoma of the skin: targeting the hedgehog pathway. protein levels within the Hh signaling pathway [35–37] Curr Opin Oncol. 2013;25(3):218–23. that could correlate with response or lack of response, with 3. Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, the ultimate goal of assisting with clinical decision- Lindgren J, Chang K, et al. Inhibiting the hedgehog pathway in making. As the current cost of SI drugs is quite high, a patients with the basal-cell nevus syndrome. N Engl J Med. 2012;386(23):2180–8. diagnostic test that could indicate the likelihood of re- 4. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas sponse to these drugs may be cost effective. JM, et al. Human homolog of patched, a candidate gene for the Many additional issues remaining to be clarified regarding basal cell nevus syndrome. Science. 1996;272:1668–71. the use of SIs, including: effective management of common 5. Taipale J, Beachy PA. The Hedgehog and Wnt signalling pathways in cancer. Nature. 2001;411(6835):349–54. side effects, long-term side effects such as the potential for 6. "Skin Cancer Foundation." Basal Cell Carcinoma (BCC). Skin secondary cancers, whether there is differential response Cancer Foundation, 2013. Web. 09 June 2013. based on BCC subtype, when SI treatment may be safely 7. Wu TP, Stein JA. Nonmelanoma skin cancer in young women. J discontinued after apparent complete clinical response, and Drugs Dermatol. 2013;12:568–72. 8. Koh D, Wang H, Lee J, Chia KS, Lee HP, Goh CL. Basal cell whether SIs should be used to treat microscopic disease in carcinoma, squamous cell carcinoma and melanoma of the skin: surgical cases where margins are positive. analysis of the Singapore Cancer Registry. Br J Dermatol. 2003;148:1161–6. 9. Weinstock MA, Fisher DE. Indoor ultraviolet tanning: what the data do and do not show regarding risk of melanoma Conclusion and keratinocyte malignancies. J Natl Compr Canc Netw. 2010;8(8):867–72. Advanced BCCs are often difficult to treat and life- 10. Nan H, Kraft P, Hunter DJ, Han J. Genetic variants in pigmentation threatening. SI drugs can be life-saving in many cases, though genes, pigmentary phenotypes, and risk of skin cancer in Caucasians. Int J Cancer. 2009;125(4):909–17. disease progression or recurrence is a major concern that 11. Alam M, Goldberg LH, Silapunt S, Gardner ES, Strom SS, requires regular monitoring through skin examinations and/ Rademaker AW, et al. Delayed treatment and continued growth of or radiologic imaging. Successful management of side effects nonmelanoma skin cancer. J Am Acad Dermatol. 2011;64(5):839– is critical to continued treatment with these drugs. When 12. Chren MM, Linos E, Torres JS, Stuart SE, Parvataeni R, Boscardin aBCCs are refractory, achieve a partial response, or are recur- WJ. Tumor recurrence 5 years after treatment of cutaneous basal rent after SI therapy, other treatment modalities such as radi- cell carcinoma and squamous cell carcinoma. J Invest Dermatol. ation, traditional chemotherapy or surgical excision need to be 2013;133:1188–96. considered for optimum patient outcomes. 13. Danial C, Lingala B, Balise R, Oro AE, Reddy S, Colevas A, Chang AL. Markedly improved overall survival in 10 consecutive meta- static basal cell carcinoma patients. Br J Dermatol 2013: 1365– Compliance with Ethics Guidelines 14. Soleymani AD, Scheinfeld N, Vasil K, Bechtel MA. Metastatic Conflict of Interest SV Mohan declares no conflicts of interest. basal cell carcinoma presenting with unilateral upper extremity ALS Chang has received research support from Genentech, Novartis, edema and lymphatic spread. J Am Acad Dermatol. 2008;59(2 Infinity, and Lilly. suppl 1):s1–3. 15. Moser S, Borm J, Mihic-Probst D, Jacobsen C, Kruse Gujer AL. Metastatic basal cell carcinoma: report of a case and Human and Animal Rights and Informed Consent This article does review of the literature. Oral Surg Oral Med Oral Pathol not contain any studies with human or animal subjects performed by any Oral Radiol 2013 of the authors. Curr Derm Rep (2014) 3:40–45 45 16. Machlin S, Carper K, Kashihara D. Health Care Expenditures for adult patients with solid tumors. Clin Cancer Res. 2013;19(10): Non-Melanoma Skin Cancer among Adults, 2005–2008 (Average 2766–74. Annual). Rockville: Agency for Healthcare Research and Quality; 34. Chang ALS, Soloman JA, Hainsworth JD, Goldberg L, McKenna 2011. E, Day B, Chen DM, Weiss GJ. Expanded access study of advanced 17. Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman basal cell carcinoma patients treated with the Hedgehog pathway SR, Fleischer AB, et al. Incidence estimate of nonmelanoma skin inhibitor, vismodegib. J Am Acad Dermatol. 2013. cancer in the United States, 2006. Arch Dermatol. 2010;146(3): 35. Li ZJ, Mack SC, Mak TH, Angers S, Taylor MD, Hui CC. Evasion 283–87. of p53 and G2/M checkpoints are characteristic of Hh-driven basal 18. Haves AW, Schaffer PR, Carucci JA. The Impact of Inoperable cell carcinoma. Oncogene 2013. Advanced Basal Cell Carcinoma: the Economic, Physical and 36. Heller ER, Gor A, Wang D, Hu Q, Lucchese A, Kanduc D, et al. Psychological Burden of the Disease. J Drugs Dermatol. Molecular signatures of basal cell carcinoma susceptibility and path- 2013;12(10):s151–53. ogenesis: a genomic approach. Int J Oncol. 2013;42(2):583–96. 19. Shingler SL, Garside J, Samanta K, Lear JT, Keohane S, Lloyd AJ. 37. Almquist LM, Karagas MR, Christensen BC, Welsh MM, Perry Utilities for advanced basal cell carcinoma. J Med Econ. AE, Storm CA, et al. The role of TP53 and MDM2 polymorphisms 2013;16(6):777–83. in TP53 mutagenesis and risk of non-melanoma skin cancer. 20. Wysong A, Aasi SZ, Tang JY. Update on metastatic basal cell Carcinogenesis. 2011;32(3):327–30. carcinoma: a summary of published cases from 1981 through 38. Kuijpers DI, Thissen MR, Berretty PJ, Ideler FH, Nelemans PJ, 2011. JAMA Dermatol. 2013;149(5):615–6. Neumann MH. Surgical excision versus curettage plus cryosurgery 21.� Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein EH, Scott MP. in the treatment of basal cell carcinoma. Dermatol Surg. Basal cell carcinomas in mice overexpressing sonic hedgehog. 2007;33(5):579–87. Science. 1997;276(5313):817–21. 39. Smeets NW, Kuijpers DI, Nelemans P, Ostertag JU, Verhaegh ME, 22. Aszterbaum M, Rothman A, Johnson RL, Fisher M, Xie J, Bonifas Krekels GA, et al. Mohs’ micrographic surgery for treatment of JM, et al. Identification of mutations in the human PATCHED gene basal cell carcinoma of the face—results of a retrospective study in sporadic basal cell carcinomas and in patients with the basal cell and review of the literature. Br J Dermatol. 2004;151(1):141–7. nevus syndrome. J Invest Derm. 1998;110(6):885–8. 40. Hamilton JR, Parvataneni R, Stuart SE, Chrem MM. Recurrence 5 23. Wollina U, Tchernev G. Advanced basal cell carcinoma. Wien Med years after treatment of recurrent cutaneous basal cell and squamous Wochenschr 2013 cell carcinoma. JAMA Dermatol. 2013;149(5):616–8. 24. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev 41. Avril MF, Auperin A, Margulis A, Gerbaulet A, Duvillard P, Cancer. 2008;8(10):743–54. Benhamou E, et al. Basal cell carcinoma of the face: surgery or 25. Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, et al. radiotherapy? Results of a randomized study. Br J Cancer. Activating Smoothened mutations in sporadic basal-cell carcinoma. 1997;76(1):100–6. Nature. 1998;391(6662):90–2. 42. Hall VL, Leppard BJ, McGill J, Kesseler ME, White JE, Goodwin 26. Skvara H, Kalthoff F, Meingassner JG, Wolff-Winiski B, Aschauer P. Treatment of basal-cell carcinoma: comparison of radiotherapy H, Kelleher JF, et al. Topical treatment of basal cell carcinomas in and cryotherapy. Clin Radiol. 1986;37(1):33–4. nevoid basal cell carcinoma syndrome with a smoothened inhibitor. 43. Amin SH, Tibes R, Kim JE, Hybarger CP. Hedgehog antagonist J Invest Dermatol. 2011;131(8):1735–44. GDC-0449 is effective in the treatment of advanced basal cell 27. Atwood SX, Chang AS, Oro AE. Hedgehog pathway inhibition and carcinoma. Laryngoscope. 2010;120(12):2456–9. the race against tumor evolution. J Cell Biol. 2012;199(2):193–7. 44. Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, 28. Keeler RF, Binns W. Teratogenic compounds of Veratrum Tibes R, et al. Inhibition of hedgehog pathway in advanced basal- Californicum Coparison of Cyclopian effects of steroidal alkaloids. cell carcinoma. N Engl J Med. 2009;361(12):1164–72. Teratology. 1968;1:5–10. 45. Moeholt K, Aagaard H, Pfeiffer P, Hansen O. Platinum-based 29. Chen JK, Taipale J, Cooper MK, Beachy PA. Inhibition of cytotoxic therapy in basal cell carcinoma a review of the literature. Hedgehog signaling by direct binding of cyclopamine to Acta Oncol. 1996;35(6):677–82. Smothened. Gene Dev. 2002;16:2743–48. 46. Guthrie TH, Porubsky ES, Luxenberg MN, Shah KJ, Wurtz KL, 30.�� Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth Watson PR. Cisplatin-based chemotherapy in advanced basal cell JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma and squamous cell carcinoma of the skin: results in 28 carcinoma. N Engl J Med. 2012;366(23):2171–9. aptients including 13 patients receiving multimodality therapy. J 31. Chang AL, Atwood SX, Tartar DM, Oro AE. Surgical excision Clin Oncol. 1990;8(2):342–6. after neoadjuvant therapy with vismodegib for a locally advanced 47. Denic S. Preoperative treatment of advanced skin carcinoma with basal cell carcinoma and resistant basal carcinomas in Gorlin syn- cisplatin and bleomycin. Am J Clin Oncol. 1999;22(1):32–4. drome. JAMA Dermatol. 2013;149(5):639–41. 48. Carneiro BA, Watkin WG, Mehta UK, Brockstein BE. Metastatic 32.� Kim J, Aftab BT, Tang JY, Kim D, Lee AH, Rezaee M, et al. basal cell carcinoma: complete response to chemotherapy and Itraconazole and arsenic trioxide inhibit hedgehog pathway activa- associated pure red cell aplasia. Cancer Invest. 2006;24(4):396– tion and tumor growth associated with acquired resistance to 400. smoothened antagonists. Cancer Cell. 2013;23(1):23–34. 49. Khandekar JD. Complete response of metastatic basal cell carcino- 33. Jimeno A, Weiss GJ, Miller WH, Gettinger S, Eigl BJ, Chang AL, ma to cisplatin chemotherapy: a report of two patients. Arch et al. Phase 1 study of the Hedgehog pathway inhibitor IPI-926 in Dermatol. 1990;126(12):1,660.

Journal

Current Dermatology ReportsPubmed Central

Published: Feb 9, 2014

There are no references for this article.