Treatments Beyond Localized Skin Surgery for BCC, SCC, and Localized Melanoma.
Basal Cell Carcinoma
BCC is the most common type of nonmelanoma skin cancer. (1) The Hedgehog (Hh) pathway is an essential regulator of growth and development during embryogenesis. This pathway usually is dormant in adulthood and is activated in several cancers, including BCC. Inhibitors of the Hh pathway have proved beneficial for BCC. (1,2)
Vismodegib was the first Hh pathway inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of adults with metastatic or locally advanced BCC. (3-5) Vismodegib has also demonstrated efficacy in inhibiting the Hh pathway in patients with basal-cell nevus (Gorlin) syndrome. (6) Toxicity (most commonly grade 1 and 2 dysgeusia, muscle cramps, hair loss, and weight loss) led roughly half the patients to stop a continuous treatment regimen in the phase 2 trial. (6) Two intermittent dosing regimens designed to improve tolerability and safety reduced the number of clinically evident BCC lesions at week 73: 63% fewer BCC lesions with schedule A, 54% fewer BCC lesions with schedule B. Nearly all (95%) patients in the trial developed treatment-related adverse events (AEs), but only 23% discontinued treatment due to AEs. (7)
Another Hh pathway inhibitor, sonidegib, is FDA-approved for the treatment of adult patients with locally advanced BCC that has recurred after surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy. (8,9) In a phase 2 trial, 36% of patients receiving a lower dose and 34% of patients receiving a higher dose had an objective response. (8)
Curettage Without Electrodesiccation
Curettage offers an option to treat small BCC tumors. Nearly all (96% of 302) BCC tumors treated with curettage by one physician showed no recurrence at 5 years. Compared with electrodesiccation, curettage alone was associated with minimal scarring and less hypopigmentation. (10) These findings are of particular interest given the recent JAMA Dermatology publication questioning the appropriate-use criteria for superficial BCCs. (11)
Squamous Cell Carcinoma
Approximately 1.5% of patients with cutaneous SCC (cSCC) will die, for an estimated total of between 4000 and 8800 US deaths in 2012. (12) An alternative staging system proposed for cSCC can improve identification of the subset of tumors with a high risk for metastasis and death. (13) Three alternative treatment options for SCC exist: topical fluorouracil (5-FU) and calcitriol, (14) intralesional methotrexate (MTX), (15) and cemiplimab. (16)
Topical 5-FU and Calcitriol
In a randomized trial involving 131 patients, applying topical 5% 5-FU cream plus 0.005% calcipotriol ointment twice daily for 4 days significantly reduced the number of actinic keratoses (mean reduction, 88% vs 26% for Vaseline[R]; P<0.0001). Participants applied the treatment to the face, scalp, and upper extremities. (14) The treatment induced thymic stromal lymphopoietin (TSLP), human leukocyte antigen (HLA) class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesionai keratinocytes. These changes were associated with marked CD4+ T-cell infiltration that peaked on days 10 to 11 after treatment, without pain, crusting, or ulceration. The investigators concluded that the synergistic effects of calcipotriol and 5-FU treatment activated CD4+ T-cell-mediated immunity against actinic keratoses. (14)
A 38-case retrospective study and literature review concluded that intralesional MTX is a beneficial nonsurgical treatment option for keratoacanthoma. Resolution occurred in 92% of cases, after a mean of 2.1 injections at a mean of 18 days apart. There were 2 reports of pancytopenia in patients with chronic renal failure. (15)
Cemiplimab is a programmed death receptor-1 blocking antibody that is FDA-approved for the treatment of patients with metastatic cSCC or locally advanced cSCC who are not candidates for curative surgery or curative radiation. (16) Results of phase 1 and phase 2 studies (NCT02383212 and NCT02760498) demonstrated response to cemiplimab in about half the patients with advanced cSCC. AEs associated with the study drug occurred in about 15% of the patients in the metastatic-disease cohort of the phase 2 study. These AEs included diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an AE. (17)
Lentigo maligna is a melanoma subtype with a good prognosis. However, it also has the highest rate of recurrence of all the subtypes when treated by surgical excision alone. Neoadjuvant imiquimod has been used off-label to reduce surgical margins in lentigo maligna. (18,19)
Although the treatment of BCC, SCC, and localized melanoma traditionally involves skin surgery, several novel alternative treatments are available for BCC, SCC, and localized melanoma.
(1.) Cirrone F. Harris CS. Vismodegib and the hedgehog pathway: a new treatment for basal cell carcinoma. Clin Ther. 2012;34(10):2039-2050.
(2.) Gould SE, Low JA. Marsters JC Jr. et al. Discovery and preclinical development of vismodegib Expert Opin Drug Discov. 2014;9(8):969-984.
(3.) Erivedge [package insert]. South San Francisco, CA: Genentech, Inc: January 2012.
(4.) Fosko SW, Chu MB. Mattox AR, Richart JM, Burkemper NM, Slutsky JB. Lichenoid reaction as a potential immune response marker of intratreatment histological response during successful vismodegib treatment for a giant basal cell carcinoma. Dermatol Ther. 2015;28(6):359-362.
(5.) Sekulic A, Migden MR. Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171 -2179.
(6.) Tang JY. Mackay-Wiggan JM. Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevns syndrome. N Engl J Med. 2012;366(23):2180-2188.
(7.) Dreno B. Kunstfeld R, Hauschild A, et al. Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (M1K1E): a randomised, regimen-controlled double-blind, phase 2 trial. Lancet Oncol. 2017;18(3):404-412.
(8.) Migden MR, Guminski A, Gutzmer R, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multi-centre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16(6):716-728.
(9.) Odomzo [package insert]. Cranbury, NJ: Sun Pharmaceutical Industries, Inc; May 2019.
(10.) Barlow JO, Zalla MJ, Kyle A, DiCaudo DJ, Lim KK, Yiannias JA. Treatment of basal cell carcinoma with curettage alone. J Am Acad Dermatol. 2006;54(6): 1039-1045.
(11.) Steinman HK, Dixon A, Zachary CB. Reevaluating Mohs surgery appropriate use criteria for primary superficial basal cell carcinoma. JA MA Dermatol. 2018; 154(7):755-756.
(12.) Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol. 2013;68(6):957-966.
(13.) Jambusaria-Pahlajani A, Kanetsky PA, Karia PS, et al. Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system. JAMA Dermatol. 2013;149(4):402-410.
(14.) Cunningham TJ, Tabacchi M, Eliane JP, et al. Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy. J Clin Invest. 2017; 127(1): 106-116.
(15.) Annest NM, VanBeek MJ, Arpey CJ, Whitaker DC, Intralesional methotrexate treatment for keratoacanthoma tumors: a retrospective study and review of the literature. J Am Acad Dermatol. 2007;56(6):989-993.
(16.) Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379(4):341-351.
(17.) Libtayo [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc; September 2018.
(18.) Fosko SW, Navarrete-Dechent CP, Nehal KS. Lentigo maligna--challenges, observations, imiquimod, confocal microscopy, and personalized treatment. JAMA Dermatol. 2018; 154(8):879-881.
(19.) Donigan JM, Hyde MA, Goldgar DE, Hadley ML, Bowling M, Bowen GM. Rate of recurrence of lentigo maligna treated with off-label neoadjuvant topical imiquimod, 5%, cream prior to conservatively staged excision. JAMA Dermatol. 2018; 154(8):885-889.
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|Author:||Zachary, Christopher B.|
|Date:||Aug 1, 2019|
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