8.7 Recent advances in the radiotherapy of skin cancer

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Clinical practice guidelines for keratinocyte cancer > 8.7 Recent advances in the radiotherapy of skin cancer


Radiotherapy (RT) modalities and approaches currently under investigation for use in the treatment of keratinocyte cancer (KC) include volumetric modulated arc therapy (VMAT) and the combination of RT with adjuvant immunotherapies.

Volumetric modulated arc therapy (background)

Intensity-modulated RT occurs when multi-leaf collimators (MLCs) within the linear accelerator (linac) gantry move in real time across the RT beam, so modulating the intensity of the beam during treatment. This is an advancement on three-dimensional conformal RT in which the beam comes in ‘blocks’. Intensity-modulated RT allows the dose volume to curve around structures such as volumes of tumour to be treated or organs to be avoided. This technology has enabled increased conformality of dose, which allows for dose escalation to tumour and dose de-escalation to normal tissue volumes, thereby increasing the therapeutic ratio.[1]

Volumetric modulated arc therapy represents a further stage of evolution towards complete dose conformality. This technology can be conceptualised as the application of computed tomography to the linac. The gantry moves in a continual arc, capable of changing the rotational velocity. Other aspects can change; the dose rate of RT coming out of the machine, and the velocity of the MLCs, leading to great precision. This type of external-beam RT is challenging brachytherapy as the ultimate conformal therapy.[2]

Results from clinical trials evaluating VMAT in the treatment of KCs are expected to become available from around mid-2019.[3]Back to top

Overview of evidence (non-systematic literature review)

Volumetric modulated arc therapy

The rotating gantry now allows difficult-to-treat volumes to be adequately irradiated without damage to nearby dose sensitive structures[4] and can be combined with systemic therapies without significant dose limiting toxicities.[5] It also allows large convex areas to be treated,[6][2][7][3] and these include areas of actinic change in which RT is effective.

Results from clinical trials evaluating VMAT in the treatment of KCs are expected to become available from around mid-2019.[3]

Tumour mutation burden

Tumour mutation burden (TMB) is associated with better survival in some skin cancers, such as Merkel cell carcinoma[8] and melanoma.[9] Immunotherapy works better in cancers with high mutational load.[9][10] Adding RT to immune therapy in the treatment of melanoma has been associated with a greater response.[11]

The TMB of KCs is the highest of any cancer type.[12] Accordingly, the combination of RT with immunotherapy in high-risk KC may increase the response. This hypothesis is likely to generate a high volume of radiobiological research.

No data are currently available from clinical trials evaluating the effect of TMB on outcomes of RT for KCs.

Adjuvant therapies

EGFR inhibitors

Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor used for the treatment of head and neck cancer in combination with RT.[13][5] Inactivation of EGFR is associated with increased radiosensitivity.[14] In the palliative setting, cetuximab as monotherapy or in combination with RT can achieve durable control of advanced cutaneous squamous cell carcinoma (cSCC).[15][16][17][18][19]

Cetuximab was associated with statistically non-significant benefit for overall survival and disease-free survival, compared with platinum-based chemotherapy, in a retrospective observational series in which patients received RT with either concomitant platinum-based chemotherapy or cetuximab as definitive (48%) or adjuvant (52%) treatment for locally advanced cSCC of head and neck.[10]

Acne-like rash is one of the more serious side effects of cetuximab therapy.[20]

Erlotinib, another EGFR inhibitor, increases local control in cSCC with RT,[21] as does gefitinib.[22]


Vismodegib is approved by the Australian Therapeutic Goods Administration for the treatment of basal cell carcinoma (BCC). It targets the hedgehog signalling pathway (which is upregulated in 90% of BCCs) and acts as a cyclopamine-competitive antagonist of the smoothened, frizzled class receptor (SMO).

Vismodegib shrinks BCCs.[23] Case reports have documented that, when combined with RT and surgery, vismodegib treatment can make BCC resectable[24] or amenable to being encompassed in an RT field,[25] or even achieve durable and acceptable stable disease.[26][27][28]

Vismodegib is particularly helpful for the treatment of patients with naevoid BCC (Gorlin’s syndrome)(naevoid BCC syndrome) an autosomal dominant syndrome characterised by multiple BCCs, in which RT is generally avoided because it can predispose to more in-field BCCs.

Vismodegib is also effective in RT-induced BCC[29] and those who have progressed through RT.[30]

Side effects can be significant, and include dysgeusia (distortion of the sense of taste) and new cSCCs.[31]

Other radiotherapy modalities

Proton and neutron therapies may also improve therapeutic ratio in locally advanced skin cancer by achieving greater conformality.[32]

A recent matched pair analysis reported that the outcomes of brachytherapy were equivalent to those of Mohs micrographic surgery in the treatment of early-stage KC.[33]

Unsealed-source brachytherapy is being trialled. Rhenium-188 as a topical therapy requires only one or two applications.[34][35]
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  1. Mattes MD, Zhou Y, Berry SL, Barker CA. Dosimetric comparison of axilla and groin radiotherapy techniques for high-risk and locally advanced skin cancer. Radiat Oncol J 2016 Jun;34(2):145-55 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27306779.
  2. 2.02.1 Santos DE, Green JA, Bhandari N, Hong A et al. Tangential Volumetric Modulated Radiotherapy - A New Technique for Large Scalp Lesions with a Case Study in Lentigo Maligna. Int J Bioautomation 2015 Jan 1;Volume 19, Number 2, 2015, pp. 223-236(14) Abstract available at https://www.ingentaconnect.com/content/doaj/13141902/2015/00000019/00000002/art00008.
  3. Fogarty GB, Christie D, Spelman LJ, Supranowicz MJ, Sinclair RS.. Can Modern Radiotherapy be used for Extensive Skin Field Cancerisation: An Update on Current Treatment Options. Biomed J Sci &Tech Res 2018;4(1).
  4. Gorayski P, Fitzgerald R, Barry T, Burmeister E, Foote M. Volumetric modulated arc therapy versus step-and-shoot intensity modulated radiation therapy in the treatment of large nerve perineural spread to the skull base: a comparative dosimetric planning study. J Med Radiat Sci 2014 Jun;61(2):85-90 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26229642.
  5. 5.05.1 Wollina U, Schreiber A, Merla K, Haroske G. Combined cetuximab and volumetric modulated arc-radiotherapy in advanced recurrent squamous cell carcinoma of the scalp. Dermatol Reports 2011 Oct 5;3(3):e57 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25386308.
  6. Lai Y, Shi L, Lin Q, Fu L, Ha H. Planning study of flattening filter free beams for volumetric modulated arc therapy in squamous cell carcinoma of the scalp. PLoS One 2014;9(12):e114953 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25506701.
  7. Lozano F, Perez N, Iglesias A, Xu X, Amendola MA, Scott M, et al. Volumetric arc therapy for total scalp irradiation: case report for a recurrent basal cell carcinoma of the scalp. Ecancermedicalscience 2017;11:737 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28596803.
  8. Vandeven N, Lewis CW, Makarov V, Riaz N, Paulson KG, Hippe D, et al. Merkel Cell Carcinoma Patients Presenting Without a Primary Lesion Have Elevated Markers of Immunity, Higher Tumor Mutation Burden, and Improved Survival. Clin Cancer Res 2018 Feb 15;24(4):963-971 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/29246939.
  9. 9.09.1 Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, et al. Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers. Mol Cancer Ther 2017 Nov;16(11):2598-2608 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28835386.
  10. 10.010.1 Lu SM, Lien WW. Concurrent Radiotherapy With Cetuximab or Platinum-based Chemotherapy for Locally Advanced Cutaneous Squamous Cell Carcinoma of the Head and Neck. Am J Clin Oncol 2018 Jan;41(1):95-99 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26353121.
  11. Theurich S, Rothschild SI, Hoffmann M, Fabri M, Sommer A, Garcia-Marquez M, et al. Local Tumor Treatment in Combination with Systemic Ipilimumab Immunotherapy Prolongs Overall Survival in Patients with Advanced Malignant Melanoma. Cancer Immunol Res 2016 Sep 2;4(9):744-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27466265.
  12. Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 2017 Apr 19;9(1):34 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28420421.
  13. Wollina U. Cetuximab in non-melanoma skin cancer. Expert Opin Biol Ther 2012 Jul;12(7):949-56 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22519406.
  14. Gracia-Cazaña T, Salazar N, Zamarrón A, Mascaraque M, Lucena SR, Juarranz Á. Resistance of Nonmelanoma Skin Cancer to Nonsurgical Treatments. Part II: Photodynamic Therapy, Vismodegib, Cetuximab, Intralesional Methotrexate, and Radiotherapy. Actas Dermosifiliogr 2016 Nov;107(9):740-750 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27436804.
  15. Conen KL, Fischer N, Hofbauer GF, Shafaeddin-Schreve B, Winterhalder R, Rochlitz C, et al. Cetuximab in metastatic squamous cell cancer of the skin: a Swiss case series. Dermatology 2014;229(2):97-101 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24923455.
  16. Giacchero D, Barrière J, Benezery K, Guillot B, Dutriaux C, Mortier L, et al. Efficacy of cetuximab for unresectable or advanced cutaneous squamous cell carcinoma--a report of eight cases. Clin Oncol (R Coll Radiol) 2011 Dec;23(10):716-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21831617.
  17. Göppner D, Nekwasil S, Franke I, Gollnick H, Leverkus M. Successful combination therapy of a locally advanced squamous cell carcinoma of the skin with cetuximab and γ-irradiation. J Dtsch Dermatol Ges 2010 Oct;8(10):826-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20731754.
  18. Samstein RM, Ho AL, Lee NY, Barker CA. Locally advanced and unresectable cutaneous squamous cell carcinoma: outcomes of concurrent cetuximab and radiotherapy. J Skin Cancer 2014;2014:284582 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25136458.
  19. Della Vittoria Scarpati G, Perri F, Pisconti S, Costa G, Ricciardiello F, Del Prete S, et al. Concomitant cetuximab and radiation therapy: A possible promising strategy for locally advanced inoperable non-melanoma skin carcinomas. Mol Clin Oncol 2016 Apr;4(4):467-471 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27073643.
  20. Merck Serono Australia Pty Ltd. Erbitux (cetuximab) Australian product information Publisher: Therapeutic Goods Administration, Australian Government Department of Health. Australian Government Department of Health; 2008 Available from: https://www.ebs.tga.gov.au/.
  21. Heath CH, Deep NL, Nabell L, Carroll WR, Desmond R, Clemons L, 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 Apr 1;85(5):1275-81 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23182701.
  22. Lewis CM, Glisson BS, Feng L, Wan F, Tang X, Wistuba II, et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res 2012 Mar 1;18(5):1435-46 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22261807.
  23. Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 2009 Sep 17;361(12):1164-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19726763.
  24. Block AM, Alite F, Diaz AZ, Borrowdale RW, Clark JI, Choi M. Combination Trimodality Therapy Using Vismodegib for Basal Cell Carcinoma of the Face. Case Rep Oncol Med 2015;2015:827608 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26504605.
  25. Gathings RM, Orscheln CS, Huang WW. Compassionate use of vismodegib and adjuvant radiotherapy in the treatment of multiple locally advanced and inoperable basal cell carcinomas and squamous cell carcinomas of the skin. J Am Acad Dermatol 2014 Apr;70(4):e88-e89 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24629372.
  26. Pollom EL, Bui TT, Chang AL, Colevas AD, Hara WY. Concurrent Vismodegib and Radiotherapy for Recurrent, Advanced Basal Cell Carcinoma. JAMA Dermatol 2015 Sep;151(9):998-1001 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25874733.
  27. Raleigh DR, Algazi A, Arron ST, Neuhaus IM, Yom SS. Induction Hedgehog pathway inhibition followed by combined-modality radiotherapy for basal cell carcinoma. Br J Dermatol 2015 Aug;173(2):544-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25702621.
  28. Schulze B, Meissner M, Ghanaati S, Burck I, Rödel C, Balermpas P. Hedgehog pathway inhibitor in combination with radiation therapy for basal cell carcinomas of the head and neck : First clinical experience with vismodegib for locally advanced disease. Strahlenther Onkol 2016 Jan;192(1):25-31 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26449347.
  29. Tauber G, Pavlovsky L, Fenig E, Hodak E. Vismodegib for radiation-induced multiple basal cell carcinomas (BCCs) of the scalp. J Am Acad Dermatol 2015 Nov;73(5):799-801 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26320385.
  30. Zargari O, Azimi SZ, Geranmayeh S. Inoperable infiltrative basal cell carcinoma successfully treated with vismodegib. Dermatol Ther 2017 Jul;30(4) Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28631369.
  31. Danhof R, Lewis K, Brown M. Small Molecule Inhibitors of the Hedgehog Pathway in the Treatment of Basal Cell Carcinoma of the Skin. Am J Clin Dermatol 2018 Apr;19(2):195-207 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28887802.
  32. Mendenhall WM, Dagan R, Bryant CM, Amdur RJ, Mancuso AA. Definitive Radiotherapy for Squamous Cell Carcinoma of the Glottic Larynx. Cancer Control 2016 Jul;23(3):208-12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27556660.
  33. Patel R, Strimling R, Doggett S, Willoughby M, Miller K, Dardick L, et al. Comparison of electronic brachytherapy and Mohs micrographic surgery for the treatment of early-stage non-melanoma skin cancer: a matched pair cohort study. J Contemp Brachytherapy 2017 Aug;9(4):338-344 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28951753.
  34. Sedda AF, Rossi G, Cipriani C, Carrozzo AM, Donati P. Dermatological high-dose-rate brachytherapy for the treatment of basal and squamous cell carcinoma. Clin Exp Dermatol 2008 Nov;33(6):745-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18681873.
  35. Epidermal Radionuclide Therapy: Dermatological High-Dose-Rate Brachytherapy for the Treatment of Basal and Squamous Cell Carcinoma In: Cipriani C, and Sedda AF. Therapeutic Nuclear Medicine; [cited 2012]. p. 725-734.

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