The mainstay of curative therapy for head and neck skin cancers relies upon surgery and/or radiation therapy. However, for some aggressive, non-resectable or recurrent tumors, systemic therapy is necessary. Recent emerging classes of drugs have shown to improve survival for high-risk, recurrent, and unresectable variants of these tumors. The goal of this paper is to review options for systemic therapies for head and neck skin cancers including melanoma, non-melanoma skin cancers and other rare and non-malignant tumors.
MarksR.An overview of skin cancers. Incidence and causation. Cancer. 1995;75:607-612.
2.
GaspariAASauderDN.Immunotherapy of basal cell carcinoma: evolving approaches. Dermatol Surg. 2003;29:1027-1034.
3.
BagheriMMSafaiB.Cutaneous malignancies of keratinocytic origin. Clin Dermatol. 2001;19:244-252.
4.
GurneyBNewlandsC. Management of regional metastatic disease in head and neck cutaneous malignancy. 1. Cutaneous squamous cell carcinoma. Br J Oral Maxillofac Surg. 2014;52:294-300.
5.
BettiRRadaelliGBombonatoCCrostiCCerriAMenniS.Anatomic location of Basal cell carcinomas may favor certain histologic subtypes. J Cutan Med Surg. 2010;14:298-302.
6.
LeibovitchIHuilgolSCSelvaDHillDRichardsSPaverR.Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years. J Am Acad Dermatol. 2005;53:253-260.
JohnsonTMRoweDENelsonBRSwansonNA.Squamous cell carcinoma of the skin (excluding lip and oral mucosa). J Am Acad Dermatol. 1992;26:467-484.
9.
KwaRECampanaKMoyRL.Biology of cutaneous squamous cell carcinoma. J Am Acad Dermatol. 1992;26:1-26.
10.
VenessMJPorcedduSPalmeCEMorganGJ.Cutaneous head and neck squamous cell carcinoma metastatic to parotid and cervical lymph nodes. Head Neck. 2007;29:621-631.
11.
LearJTTanBBSmithAG, et al. Risk factors for basal cell carcinoma in the UK: case-control study in 806 patients. J R Soc Med. 1997;90:371-374.
12.
KaragasMRStukelTAGreenbergERBaronJAMottLASternRS.Risk of subsequent basal cell carcinoma and squamous cell carcinoma of the skin among patients with prior skin cancer. Skin Cancer Prevention Study Group. JAMA. 1992;267:3305-2210.
13.
RamachandranSFryerAALovattTJ, et al. Combined effects of gender, skin type and polymorphic genes on clinical phenotype: use of rate of increase in numbers of basal cell carcinomas as a model system. Cancer Lett. 2003;189:175-181.
ZieglerAJonasonASLeffellDJ, et al. Sunburn and p53 in the onset of skin cancer. Nature. 1994;372:773-776.
16.
PalmeCEO’BrienCJVenessMJMcNeilEBBronLPMorganGJ.Extent of parotid disease influences outcome in patients with metastatic cutaneous squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2003;129:750-753.
17.
RoweDECarrollRJDayCLJr.Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 1992;26:976-990.
18.
MoloneyFJComberHO’LorcainPO’KellyPConlonPJMurphyGM.A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol. 2006;154:498-504.
19.
NguyenPVin-ChristianKMingMEBergerT.Aggressive squamous cell carcinomas in persons infected with the human immunodeficiency virus. Arch Dermatol. 2002;138:758-763.
20.
HayashiMTamuraGKatoNAnsaiSKondoSMotoyamaT.Genetic analysis of cutaneous squamous cell carcinomas arising from different areas. Pathol Int. 2003;53:602-607.
21.
HarwoodCASurentheranTSasieniP, et al. Increased risk of skin cancer associated with the presence of epidermodysplasia verruciformis human papillomavirus types in normal skin. Br J Dermatol. 2004;150:949-957.
22.
GoldmanGD.Squamous cell cancer: a practical approach. Semin Cutan Med Surg. 1998;17: 80-95.
23.
EklundJWKuzelTM.A review of recent findings involving interleukin-2-based cancer therapy. Curr Opin Oncol. 2004;16:542-546.
24.
EggermontAMSuciuSSantinamiM, et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet. 2008;372:117-126.
25.
Pilon-ThomasSKuhnLEllwangerS, et al. Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma. J Immunother. 2012;35:615-620.
26.
RosenbergSAYangJCSherryRM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17:4550-4557.
27.
KirkwoodJMManolaJIbrahimJ, et al. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004;10:1670-1677.
28.
MocellinSPasqualiSRossiCRNittiD.Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010;102: 493-501.
29.
MocellinSLensMBPasqualiSPilatiPChiarion SileniV.Interferon alpha for the adjuvant treatment of cutaneous melanoma. Cochrane Database Syst Rev. 2013;6:CD008955.
30.
SchwartzentruberDJLawsonDHRichardsJM, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364:2119-2127.
31.
YaoSZhuYChenL.Advances in targeting cell surface signalling molecules for immune modulation. Nat Rev Drug Discov. 2013;12:130-146.
32.
WolchokJDNeynsBLinetteG, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155-164.
33.
HodiFSO’DaySJMcDermottDF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.
34.
BuchbinderEIDesaiA.CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39:98-106.
35.
CallahanMKWolchokJD.At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. J Leukoc Biol. 2013;94:41-53.
36.
WalkerLSSansomDM.The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol. 2011;11:852-863.
37.
EggermontAMChiarion-SileniVGrobJJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845-1855.
38.
KwakMFarrowNESalamaAKS, et al. Updates in adjuvant systemic therapy for melanoma. J Surg Oncol. 2019;119:222-231.
39.
EggermontAMChiarion-SileniVGrobJJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16:522-530.
40.
AsciertoPADel VecchioMRobertC, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017;18:611-622.
41.
TopalianSLDrakeCGPardollDM.Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207-212.
42.
BalarAVWeberJS.PD-1 and PD-L1 antibodies in cancer: current status and future directions. Cancer Immunol Immunother. 2017;66:551-564.
43.
RibasAHamidODaudA, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315:1600-1609.
44.
WolchokJDChiarion-SileniVGonzalezR, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377:1345-1356.
45.
LarkinJChiarion-SileniVGonzalezR, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381:1535-1546.
46.
HodiFSChesneyJPavlickAC, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17:1558-1568.
47.
WeberJMandalaMDel VecchioM, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017;377:1824-1835.
48.
AsciertoPADel VecchioMMandalaM, et al. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020;21:1465-1477.
49.
EggermontAMMBlankCUMandalaM, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378:1789-1801.
50.
RobertCThomasLBondarenkoI, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.
51.
SnyderAMakarovVMerghoubT, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189-2199.
52.
HamidORobertCDaudA, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134-144.
53.
WangJChmielowskiBPellissierJXuRStevinsonKLiuFX.Cost-effectiveness of pembrolizumab versus ipilimumab in ipilimumab-naive patients with advanced melanoma in the United States. J Manag Care Spec Pharm. 2017;23:184-194.
MorrisonCPablaSConroyJM, et al. Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden. J Immunother Cancer. 2018;6:32.
56.
KohlhappFJKaufmanHL.Molecular pathways: mechanism of action for talimogene laherparepvec, a new oncolytic virus immunotherapy. Clin Cancer Res. 2016;22:1048-1054.
57.
HercusTRThomasDGuthridgeMA, et al. The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood. 2009;114:1289-1298.
58.
AgarwalaSS.Intralesional therapy for advanced melanoma: promise and limitation. Curr Opin Oncol. 2015;27:151-156.
59.
HoellerCMichielinOAsciertoPASzaboZBlankCU.Systematic review of the use of granulocyte-macrophage colony-stimulating factor in patients with advanced melanoma. Cancer Immunol Immunother. 2016;65:1015-1034.
60.
DummerRHoellerCGruterIPMichielinO.Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors. Cancer Immunol Immunother. 2017;66:683-695.
61.
PuzanovIMilhemMMMinorD, et al. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma. J Clin Oncol. 2016;34:2619-2626.
62.
ChesneyJPuzanovICollichioF, et al. Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J Clin Oncol. 2018;36:1658-1667.
63.
RibasADummerRPuzanovI, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell. 2017;170:1109-1119.e10.
64.
SunLFunchainPSongJM, et al. Talimogene laherparepvec combined with anti-PD-1 based immunotherapy for unresectable stage III-IV melanoma: a case series. J Immunother Cancer. 2018;6:36.
65.
DaviesHBignellGRCoxC, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-954.
66.
HauschildAGrobJJDemidovLV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358-365.
67.
McArthurGAChapmanPBRobertC, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014; 15: 323-332.
68.
FlahertyKTRobertCHerseyP, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-114.
69.
FlahertyKTInfanteJRDaudA, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694-1703.
70.
LongGVHauschildASantinamiM, et al. Adjuvant Dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813-1823.
71.
LongGVFlahertyKTStroyakovskiyD, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28:1631-1639.
72.
AsciertoPAMcArthurGADrenoB, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17:1248-1260.
73.
DummerRAsciertoPAGogasHJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19:603-615.
74.
DummerRAsciertoPAGogasHJ, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19:1315-1327.
75.
AlgaziAPOthusMDaudAI, et al. Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial. Nat Med. 2020;26:1564-1568.
76.
ZimmerLHillenULivingstoneE, et al. Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol. 2012;30:2375-2383.
77.
GibneyGTMessinaJLFedorenkoIVSondakVKSmalleyKS.Paradoxical oncogenesis–the long-term effects of BRAF inhibition in melanoma. Nat Rev Clin Oncol. 2013;10:390-399.
78.
PuzanovIRibasARobertC, et al. Association of BRAF V600E/K mutation status and prior BRAF/MEK inhibition with pembrolizumab outcomes in advanced melanoma: pooled analysis of 3 clinical trials. JAMA Oncol. 2020;6:1256-1264.
79.
LarkinJLaoCDUrbaWJ, et al. Efficacy and safety of nivolumab in patients with BRAF V600 mutant and BRAF wild-type advanced melanoma: a pooled analysis of 4 clinical trials. JAMA Oncol. 2015;1:433-440.
80.
JohnsonDBPectasidesEFeldE, et al. Sequencing treatment in BRAFV600 mutant melanoma: anti-PD-1 before and after BRAF inhibition. J Immunother. 2017;40:31-35.
81.
MasonRDeardenHCNguyenB, et al. Combined ipilimumab and nivolumab first-line and after BRAF-targeted therapy in advanced melanoma. Pigment Cell Melanoma Res. 2020;33:358-365.
82.
HiganoCSSchellhammerPFSmallEJ, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009;115:3670-3679.
83.
HerseyPCoatesASMcCarthyWH, et al. Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial. J Clin Oncol. 2002;20:4181-4190.
84.
TestoriARichardsJWhitmanE, et al. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician’s choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol. 2008;26:955-962.
85.
van ZeijlMCvan den EertweghAJHaanenJBWoutersMW.(Neo)adjuvant systemic therapy for melanoma. Eur J Surg Oncol. 2017;43:534-543.
86.
FerlayJSoerjomataramIDikshitR, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359-E386.
87.
SiegelRLMillerKDJemalA.Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7-30.
88.
RubinAIChenEHRatnerD.Basal-cell carcinoma. N Engl J Med. 2005;353:2262-2269.
89.
LearWDahlkeEMurrayCA.Basal cell carcinoma: review of epidemiology, pathogenesis, and associated risk factors. J Cutan Med Surg. 2007;11:19-30.
90.
TaipaleJBeachyPA.The Hedgehog and Wnt signalling pathways in cancer. Nature. 2001;411:349-354.
91.
HutchinMEKariapperMSGrachtchoukM, et al. Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle. Genes Dev. 2005; 19: 214-223.
92.
GoppnerDLeverkusM.Basal cell carcinoma: from the molecular understanding of the pathogenesis to targeted therapy of progressive disease. J Skin Cancer. 2011;2011:650258.
93.
OtsukaALevesqueMPDummerRKabashimaK.Hedgehog signaling in basal cell carcinoma. J Dermatol Sci. 2015;78:95-100.
94.
BakshiAChaudharySCRanaMElmetsCAAtharM.Basal cell carcinoma pathogenesis and therapy involving hedgehog signaling and beyond. Mol Carcinog. 2017;56:2543-2557.
95.
AszterbaumMRothmanAJohnsonRL, et al. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J Invest Dermatol. 1998;110:885-888.
96.
RaleighDRAlgaziAArronSTNeuhausIMYomSS.Induction Hedgehog pathway inhibition followed by combined-modality radiotherapy for basal cell carcinoma. Br J Dermatol. 2015;173:544-546.
97.
Basset-SeguinNHauschildAGrobJJ, et al. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial. Lancet Oncol. 2015; 16: 729-376.
98.
SekulicAMigdenMROroAE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171-2179.
99.
CooperJSPajakTFForastiereAA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350:1937-1944.
100.
MigdenMRGuminskiAGutzmerR, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16:716-728.
101.
DummerRGuminskiAGutzmerR, et al. The 12-month analysis from Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT): a phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma. J Am Acad Dermatol. 2016;75:113-125.e5.
102.
SharpeHJPauGDijkgraafGJ, et al. Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma. Cancer Cell. 2015;27:327-341.
103.
IkedaSGoodmanAMCohenPR, et al. Metastatic basal cell carcinoma with amplification of PD-L1: exceptional response to anti-PD1 therapy. NPJ Genom Med. 2016;1:16037.
104.
LipsonEJLiloMTOgurtsovaA, et al. Basal cell carcinoma: PD-L1/PD-1 checkpoint expression and tumor regression after PD-1 blockade. J Immunother Cancer. 2017;5:23.
105.
FalchookGSLeidnerRStankevichE, et al. Responses of metastatic basal cell and cutaneous squamous cell carcinomas to anti-PD1 monoclonal antibody REGN2810. J Immunother Cancer. 2016;4:70.
106.
MohanSVKuoKYChangAL.Incidental regression of an advanced basal cell carcinoma after ipilimumab exposure for metastatic melanoma. JAAD Case Rep. 2016;2:13-5.
107.
GoodmanAMKatoSCohenPR, et al. Genomic landscape of advanced basal cell carcinoma: Implications for precision treatment with targeted and immune therapies. Oncoimmunology. 2018;7:e1404217.
108.
SabbatinoFMarraALiguoriL, et al. Resistance to anti-PD-1-based immunotherapy in basal cell carcinoma: a case report and review of the literature. J Immunother Cancer. 2018;6:126.
109.
DurinckSHoCWangNJ, et al. Temporal dissection of tumorigenesis in primary cancers. Cancer Discov. 2011;1:137-143.
110.
SouthAPPurdieKJWattSA, et al. NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis. J Invest Dermatol. 2014;134:2630-2638.
111.
AlterMSatzgerIMatternAKappAGutzmerR.Treatment of advanced cutaneous squamous cell carcinomas with epidermal growth factor receptor inhibitors. Dermatology. 2013;227:289-294.
112.
JostMKariCRodeckU.The EGF receptor - an essential regulator of multiple epidermal functions. Eur J Dermatol. 2000;10:505-510.
113.
GalerCECoreyCLWangZ, et al. Dual inhibition of epidermal growth factor receptor and insulin-like growth factor receptor I: reduction of angiogenesis and tumor growth in cutaneous squamous cell carcinoma. Head Neck. 2011;33:189-198.
114.
Rubin GrandisJMelhemMFGoodingWE, et al. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst. 1998;90:824-832.
115.
AngKKBerkeyBATuX, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62:7350-7356.
116.
WollinaU.Update of cetuximab for non-melanoma skin cancer. Expert Opin Biol Ther. 2014;14:271-276.
117.
KimSEleffMNicolaouN.Cetuximab as primary treatment for cutaneous squamous cell carcinoma to the neck. Head Neck. 2011;33:286-288.
118.
MaubecEPetrowPScheer-SenyarichI, et al. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol. 2011;29:3419-3426.
119.
ShaibWKonoSSabaN.Antiepidermal growth factor receptor therapy in squamous cell carcinoma of the head and neck. J Oncol. 2012;2012:521215.
120.
RebucciMPeixotoPDewitteA, et al. Mechanisms underlying resistance to cetuximab in the HNSCC cell line: role of AKT inhibition in bypassing this resistance. Int J Oncol. 2011;38:189-200.
121.
HeathCHDeepNLNabellL, et al. Phase 1 study of erlotinib plus radiation therapy in patients with advanced cutaneous squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2013;85:1275-1281.
122.
LewisCMGlissonBSFengL, et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res. 2012;18:1435-1446.
123.
MigdenMRRischinDSchmultsCD, et al. PD-1 Blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379:341-351.
124.
RischinDMigdenMRLimAM, et al. Phase 2 study of cemiplimab in patients with metastatic cutaneous squamous cell carcinoma: primary analysis of fixed-dosing, long-term outcome of weight-based dosing. J Immunother Cancer. 2020;8:e000775.
125.
DayFKumarMFentonLGedyeC.Durable response of metastatic squamous cell carcinoma of the skin to ipilimumab immunotherapy. J Immunother. 2017;40:36-38.
126.
FitzgeraldTLDennisSKachareSDVohraNAWongJHZervosEE.Dramatic Increase in the Incidence and Mortality from Merkel Cell Carcinoma in the United States. Am Surg. 2015;81:802-806.
127.
BichakjianCKLoweLLaoCD, et al. Merkel cell carcinoma: critical review with guidelines for multidisciplinary management. Cancer. 2007;110:1-12.
128.
AllenPJBowneWBJaquesDPBrennanMFBusamKCoitDG.Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol. 2005;23:2300-2309.
129.
NghiemPKaufmanHLBharmalMMahnkeLPhatakHBeckerJC.Systematic literature review of efficacy, safety and tolerability outcomes of chemotherapy regimens in patients with metastatic Merkel cell carcinoma. Future Oncol. 2017;13:1263-1279.
130.
KaufmanHLHungerMHennessyMSchlichtingMBharmalM.Nonprogression with avelumab treatment associated with gains in quality of life in metastatic Merkel cell carcinoma. Future Oncol. 2018;14:255-266.
131.
NghiemPTBhatiaSLipsonEJ, et al. PD-1 blockade with pembrolizumab in advanced merkel-cell carcinoma. N Engl J Med. 2016;374:2542-2552.
KaufmanHLRussellJHamidO, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17:1374-1385.
136.
LaraKMInGKMatcukGRJrMehtaAHuJS. Talimogene laherparepvec in combination with pembrolizumab leads to a complete response in a patient with refractory Merkel cell carcinoma. JAAD Case Rep. 2018;4:1004-1006.
137.
KnackstedtRSussmanTAMcCahonLSongJMFunchainPGastmanB.Pre-treated anti-PD-1 refractory Merkel cell carcinoma successfully treated with the combination of PD-1/PD-L1 axis inhibitors and TVEC: a report of two cases. Ann Oncol. 2019;30:1399-1400.
SegalNHHeARDoiT, et al. Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res. 2018;24:1816-1823.
140.
DresangLRGuastafierroAAroraRNormolleDChangYMoorePS.Response of Merkel cell polyomavirus-positive merkel cell carcinoma xenografts to a survivin inhibitor. PLoS One. 2013;8:e80543.
141.
AroraRShudaMGuastafierroA, et al. Survivin is a therapeutic target in Merkel cell carcinoma. Sci Transl Med. 2012;4:133ra56.
142.
VerhaegenMEMangelbergerDWeickJW, et al. Merkel cell carcinoma dependence on bcl-2 family members for survival. J Invest Dermatol. 2014;134:2241-2250.
143.
BuderKLapaCKreisslMC, et al. Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging. BMC Cancer. 2014;14:268.
144.
KwekkeboomDJHoffAMLambertsSWOeiHYKrenningEP.Somatostatin analogue scintigraphy. A simple and sensitive method for the in vivo visualization of Merkel cell tumors and their metastases. Arch Dermatol. 1992;128:818-821.
145.
PatelSHHaydenREHinniML, et al. Angiosarcoma of the scalp and face: the Mayo Clinic experience. JAMA Otolaryngol Head Neck Surg. 2015;141:335-340.
146.
OgawaKTakahashiKAsatoY, et al. Treatment and prognosis of angiosarcoma of the scalp and face: a retrospective analysis of 48 patients. Br J Radiol. 2012;85:e1127-e1133.
147.
ChoiJHAhnKCChangHMinnKWJinUSKimBJ.Surgical treatment and prognosis of angiosarcoma of the scalp: a retrospective analysis of 14 patients in a single institution. Biomed Res Int. 2015;2015:321896.
148.
PawlikTMPaulinoAFMcGinnCJ, et al. Cutaneous angiosarcoma of the scalp: a multidisciplinary approach. Cancer. 2003;98:1716-1726.
149.
ShinJYRohSGLeeNHYangKM.Predisposing factors for poor prognosis of angiosarcoma of the scalp and face: Systematic review and meta-analysis. Head Neck. 2017;39:380-386.
150.
BuschmannALehnhardtMTomanNPreilerPSalakdehMSMuehlbergerT.Surgical treatment of angiosarcoma of the scalp: less is more. Ann Plast Surg. 2008;61:399-403.
151.
AlqumberNAChoiJWKangMK.The management and prognosis of facial and scalp angiosarcoma: a retrospective analysis of 15 patients. Ann Plast Surg. 2019;83:55-62.
152.
HwangKKimMYLeeSH.Recommendations for therapeutic decisions of angiosarcoma of the scalp and face. J Craniofac Surg. 2015;26:e253-e256.
153.
FujisawaYYoshinoKFujimuraT, et al. Cutaneous angiosarcoma: the possibility of new treatment options especially for patients with large primary tumor. Front Oncol. 2018;8:46.
154.
FujisawaYNakamuraYKawachiYOtsukaF.Comparison between taxane-based chemotherapy with conventional surgery-based therapy for cutaneous angiosarcoma: a single-center experience. J Dermatolog Treat. 2014;25:419-423.
155.
GuadagnoloBAZagarsGKAraujoDRaviVShellenbergerTDSturgisEM.Outcomes after definitive treatment for cutaneous angiosarcoma of the face and scalp. Head Neck. 2011;33:661-667.
156.
StewardWPVerweijJSomersR, et al. Doxorubicin plus ifosfamide with rhGM-CSF in the treatment of advanced adult soft-tissue sarcomas: preliminary results of a phase II study from the EORTC Soft-Tissue and Bone Sarcoma Group. J Cancer Res Clin Oncol. 1991;117(suppl 4):S193-S197.
157.
PenelNBuiBNBayJO, et al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol. 2008;26:5269-5274.
158.
Ray-CoquardILDomontJTresch-BruneelE, et al. Paclitaxel given once per week with or without bevacizumab in patients with advanced angiosarcoma: a randomized phase II trial. J Clin Oncol. 2015;33:2797-2802.
159.
WilliamsVCLucasJBabcockMAGutmannDHKorfBMariaBL.Neurofibromatosis type 1 revisited. Pediatrics. 2009;123:124-133.
160.
ViskochilDWhiteRCawthonR.The neurofibromatosis type 1 gene. Annu Rev Neurosci. 1993;16:183-205.
161.
JessenWJMillerSJJousmaE, et al. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest. 2013;123:340-347.
162.
DombiEBaldwinAMarcusLJ, et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med. 2016;375:2550-2560.
163.
GrossAMWoltersPLDombiE, et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med. 2020;382:1430-1442.