Emerging Trends in the Treatment of Advanced Basal Cell Carcinoma Michael R. Migden, Anne Lynn S. Chang, Luc Dirix, Alexander J. Stratigos, John T. Lear  Cancer Treatment Reviews  DOI: 10.1016/j.ctrv.2017.12.009 Copyright © 2017 Terms and Conditions

Fig. 1 Basal cell carcinoma (BCC) treatment guidelines from (A) the European Dermatology Forum [9] and (B) the National Comprehensive Cancer Network (NCCN) [8]. In the European Dermatology Forum Guidelines, low-risk BCC includes superficial primary BCC, nodular primary BCC that is < 1 cm (intermediate-risk area) or < 2 cm (low-risk area), and Pinkus tumor BCC; intermediate risk BCC includes superficial recurrent BCC and nodular primary BCC that is < 1 cm (high-risk area), > 1 cm (intermediate-risk area), or > 2 cm (low-risk area); high-risk BCC includes morpheaform or ill-defined BCC, nodular primary BCC that is > 1 cm (high-risk area), aggressive histological forms of BCC, and nonsuperficial recurrent BCC. In the NCCN Guidelines, low-risk BCC includes nodular/superficial/nonaggressive primary BCC that is < 2 cm (area L) or < 1 cm (area M; location independent of size may constitute high risk) with well-defined borders, without perineural involvement, in sites without prior radiotherapy, and in patients without immunosuppression; any other BCC is considered high risk. Although categorized as high risk based on location, other treatment modalities may be considered for tumors < 0.6 cm in area H without other high-risk features if ≥ 0.4-cm clinically tumor-free margins are obtainable without significant anatomic or functional distortions. Panel A is reprinted with permission from Trakatelli M, et al. Eur J Dermatol. 2014;24(3):312-329. Copyright © 2017 John Libbey Eurotext. Panel B is adapted (permission pending) from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Basal Cell Skin Cancer V.1.2017. © 2017 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 5-FU = 5-fluorouracil, FDA = US Food and Drug Administration, H&P = history and physical examination, HPI = hedgehog pathway inhibitor, MRI = magnetic resonance therapy, PDT = photodynamic therapy, RT = radiotherapy. a See NCCN Guidelines® for additional information on risk factors for recurrence, principles of treatment for BCC, and principles of radiation therapy for BCC. b Excision with complete circumferential peripheral and deep margin assessment with frozen or permanent section is an alternative to Mohs micrographic surgery. c Area L = trunk and extremities (excluding pretibial, hands, feet, nail units, and ankles). d Closures like adjacent tissue transfers, in which significant tissue rearrangement occurs, are best performed after clear margins are verified. e RT is often reserved for patients over 60 years because of concerns about long-term sequalae. f Any high-risk factor places the patient in the high-risk category. g For complicated cases, consider multidisciplinary tumor board consultation. h Negative margins unachievable by Mohs micrographic surgery or more extensive surgical procedures. i Current FDA-approved hedgehog pathway inhibitors include vismodegib and sonidegib. j If large nerve involvement is suspected, consider MRI with contrast to evaluate extent and rule out base of skull involvement or intracranial extension in head and neck tumors. k There are conflicting data about the value of adjuvant RT following margin-negative surgical excision, particularly after Mohs micrographic surgery. l Due to the wide variability of clinical characteristics that may define a high-risk tumor, it is not feasible to recommend a defined margin for standard excision of high-risk BCC. Keen awareness of the subclinical extension of BCC is advised when selecting a treatment modality without complete margin assessment for a high-risk tumor. These margins may need to be modified based on tumor- or patient-specific factors. m If surgery and RT are contraindicated, consider multidisciplinary tumor board consultation and therapy. Cancer Treatment Reviews DOI: (10.1016/j.ctrv.2017.12.009) Copyright © 2017 Terms and Conditions

Fig. 1 Basal cell carcinoma (BCC) treatment guidelines from (A) the European Dermatology Forum [9] and (B) the National Comprehensive Cancer Network (NCCN) [8]. In the European Dermatology Forum Guidelines, low-risk BCC includes superficial primary BCC, nodular primary BCC that is < 1 cm (intermediate-risk area) or < 2 cm (low-risk area), and Pinkus tumor BCC; intermediate risk BCC includes superficial recurrent BCC and nodular primary BCC that is < 1 cm (high-risk area), > 1 cm (intermediate-risk area), or > 2 cm (low-risk area); high-risk BCC includes morpheaform or ill-defined BCC, nodular primary BCC that is > 1 cm (high-risk area), aggressive histological forms of BCC, and nonsuperficial recurrent BCC. In the NCCN Guidelines, low-risk BCC includes nodular/superficial/nonaggressive primary BCC that is < 2 cm (area L) or < 1 cm (area M; location independent of size may constitute high risk) with well-defined borders, without perineural involvement, in sites without prior radiotherapy, and in patients without immunosuppression; any other BCC is considered high risk. Although categorized as high risk based on location, other treatment modalities may be considered for tumors < 0.6 cm in area H without other high-risk features if ≥ 0.4-cm clinically tumor-free margins are obtainable without significant anatomic or functional distortions. Panel A is reprinted with permission from Trakatelli M, et al. Eur J Dermatol. 2014;24(3):312-329. Copyright © 2017 John Libbey Eurotext. Panel B is adapted (permission pending) from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Basal Cell Skin Cancer V.1.2017. © 2017 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 5-FU = 5-fluorouracil, FDA = US Food and Drug Administration, H&P = history and physical examination, HPI = hedgehog pathway inhibitor, MRI = magnetic resonance therapy, PDT = photodynamic therapy, RT = radiotherapy. a See NCCN Guidelines® for additional information on risk factors for recurrence, principles of treatment for BCC, and principles of radiation therapy for BCC. b Excision with complete circumferential peripheral and deep margin assessment with frozen or permanent section is an alternative to Mohs micrographic surgery. c Area L = trunk and extremities (excluding pretibial, hands, feet, nail units, and ankles). d Closures like adjacent tissue transfers, in which significant tissue rearrangement occurs, are best performed after clear margins are verified. e RT is often reserved for patients over 60 years because of concerns about long-term sequalae. f Any high-risk factor places the patient in the high-risk category. g For complicated cases, consider multidisciplinary tumor board consultation. h Negative margins unachievable by Mohs micrographic surgery or more extensive surgical procedures. i Current FDA-approved hedgehog pathway inhibitors include vismodegib and sonidegib. j If large nerve involvement is suspected, consider MRI with contrast to evaluate extent and rule out base of skull involvement or intracranial extension in head and neck tumors. k There are conflicting data about the value of adjuvant RT following margin-negative surgical excision, particularly after Mohs micrographic surgery. l Due to the wide variability of clinical characteristics that may define a high-risk tumor, it is not feasible to recommend a defined margin for standard excision of high-risk BCC. Keen awareness of the subclinical extension of BCC is advised when selecting a treatment modality without complete margin assessment for a high-risk tumor. These margins may need to be modified based on tumor- or patient-specific factors. m If surgery and RT are contraindicated, consider multidisciplinary tumor board consultation and therapy. Cancer Treatment Reviews DOI: (10.1016/j.ctrv.2017.12.009) Copyright © 2017 Terms and Conditions