Background. Advanced age and immune dysfunction are risk factors for cutaneous squamous cell carcinoma (cSCC) and often render patients with locally-advanced disease medically inoperable or surgically unresectable, but potentially curable with radiotherapy. Concurrent chemotherapy and radiotherapy may not be well tolerated in this population, but another systemic therapy may improve disease control. Objective. Determine the tolerance and efficacy of concurrent cetuximab and radiotherapy (CRT) for patients with locally advanced and unresectable cSCC. Methods. Retrospective analysis of 12 patients treated with CRT for locally advanced and unresectable cSCC. Results. Patients were elderly and 75% had moderate-to-severe comorbidities, while 42% had immune dysfunction. Grades 3-4 adverse events were noted in 83% of patients; 67% required hospital admission for adverse events. Complete and partial response was noted in 36% and 27% (response rate, 64%). Stable and progressive disease was noted in 3 and 1 patients, respectively (disease control rate, 91%). Median progression-free and overall survival were 6.4 and 8.0 months, respectively. Limitations. Retrospective small-cohort, single-institution analysis. Conclusion. Patients selected for CRT were elderly, with comorbidities and immune dysfunction, but treatment responses were observed. Patients selected for this treatment approach have a poor prognosis with limited capacity for therapy; more effective treatment is needed. 1. Introduction Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in the United States with an increasing incidence over the past few decades. The disease often presents at an early stage and is controlled with surgical, radiation, topical, or photodynamic therapy. Advanced age and immune dysfunction are risk factors for cSCC and render some patients medically unfit for surgery at diagnosis or recurrence. Moreover, some patients present with extensive local invasion or metastasis, rendering the cSCC surgically unresectable. Patients with locally advanced cSCC that are medically inoperable or surgically unresectable have a poor prognosis but can be cured with radiotherapy [1, 2]. Improving the outcome of radiotherapy through the use of concurrent systemic therapy has been demonstrated in several locally advanced cancer-treatment paradigms. Platinum (e.g., cisplatin, carboplatin) and halogenated pyrimidine (e.g., 5-fluorouracil) chemotherapies are frequently used in conjunction with radiotherapy to improve treatment efficacy but may not be well tolerated by patients
References
[1]
M. Alam and D. Ratner, “Cutaneous squamous-cell carcinoma,” The New England Journal of Medicine, vol. 344, no. 13, pp. 975–983, 2001.
[2]
M. O. F. Al-Othman, W. M. Mendenhall, and R. J. Amdur, “Radiotherapy alone for clinical T4 skin carcinoma of the head and neck with surgery reserved for salvage,” The American Journal of Otolaryngology—Head and Neck Medicine and Surgery, vol. 22, no. 6, pp. 387–390, 2001.
[3]
T. Y. Seiwert, J. K. Salama, and E. E. Vokes, “The concurrent chemoradiation paradigm—general principles,” Nature Clinical Practice Oncology, vol. 4, no. 2, pp. 86–100, 2007.
[4]
N. Normanno, A. de Luca, C. Bianco et al., “Epidermal growth factor receptor (EGFR) signaling in cancer,” Gene, vol. 366, no. 1, pp. 2–16, 2006.
[5]
G. B. Fogarty, N. M. Conus, J. Chu, and G. McArthur, “Characterization of the expression and activation of the epidermal growth factor receptor in squamous cell carcinoma of the skin,” British Journal of Dermatology, vol. 156, no. 1, pp. 92–98, 2007.
[6]
P. Uribe and S. Gonzalez, “Epidermal growth factor receptor (EGFR) and squamous cell carcinoma of the skin: molecular bases for EGFR-targeted therapy,” Pathology Research and Practice, vol. 207, no. 6, pp. 337–342, 2011.
[7]
A. Toll, R. Salgado, M. Yébenes et al., “Epidermal growth factor receptor gene numerical aberrations are frequent events in actinic keratoses and invasive cutaneous squamous cell carcinomas,” Experimental Dermatology, vol. 19, no. 2, pp. 151–153, 2010.
[8]
E. Maubec, P. Duvillard, V. Velasco, B. Crickx, and M. F. Avril, “Immunohistochemical analysis of EGFR and HER-2 in patients with metastatic squamous cell carcinoma of the skin,” Anticancer Research, vol. 25, no. 2, pp. 1205–1210, 2005.
[9]
S. Ch'ng, I. Low, D. Ng et al., “Epidermal growth factor receptor: a novel biomarker for aggressive head and neck cutaneous squamous cell carcinoma,” Human Pathology, vol. 39, no. 3, pp. 344–349, 2008.
[10]
E. Maubec, P. Petrow, I. Scheer-Senyarich et al., “Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin,” Journal of Clinical Oncology, vol. 29, no. 25, pp. 3419–3426, 2011.
[11]
S. Preneau, E. Rio, A. Brocard et al., “Efficacy of cetuximab in the treatment of squamous cell carcinoma,” The Journal of Dermatological Treatment, vol. 25, no. 5, pp. 424–427, 2014.
[12]
J. A. Bonner, P. M. Harari, J. Giralt et al., “Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck,” The New England Journal of Medicine, vol. 354, no. 6, pp. 567–578, 2006.
[13]
J. A. Bonner, P. M. Harari, J. Giralt et al., “Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival,” The Lancet Oncology, vol. 11, no. 1, pp. 21–28, 2010.
[14]
S. Huang, J. M. Bock, and P. M. Harari, “Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck,” Cancer Research, vol. 59, no. 8, pp. 1935–1940, 1999.
[15]
G. R. Blumenschein Jr., R. Paulus, W. J. Curran et al., “Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small-cell lung cancer: RTOG 0324,” Journal of Clinical Oncology, vol. 29, no. 17, pp. 2312–2318, 2011.
[16]
L. O. Olivatto, F. M. Vieira, B. V. Pereira et al., “Phase 1 study of cetuximab in combination with 5-fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma,” Cancer, vol. 119, no. 16, pp. 2973–2980, 2013.
[17]
H. Safran, M. Suntharalingam, T. Dipetrillo et al., “Cetuximab with concurrent chemoradiation for esophagogastric cancer: assessment of toxicity,” International Journal of Radiation Oncology Biology Physics, vol. 70, no. 2, pp. 391–395, 2008.
[18]
K. N. Moore, M. W. Sill, D. S. Miller et al., “A phase i trial of tailored radiation therapy with concomitant cetuximab and cisplatin in the treatment of patients with cervical cancer: a gynecologic oncology group study,” Gynecologic Oncology, vol. 127, no. 3, pp. 456–461, 2012.
[19]
W. L. Read, R. M. Tierney, N. C. Page et al., “Differential prognostic impact of comorbidity,” Journal of Clinical Oncology, vol. 22, no. 15, pp. 3099–3103, 2004.
[20]
S. B. Edge and American Joint Committee on Cancer, AJCC Cancer Staging Manual, Springer, New York, NY, USA, 2010.
[21]
National Cancer Institute (U.S.), Common Terminology Criteria for Adverse Events (CTCAE), U.S. Deptartment of Health and Human Services, National Institutes of Health, National Cancer Institute, Bethesda, Md, USA, 2009.
[22]
M. R. Kanakamedala, S. Packianathan, and S. Vijayakumar, “Lack of Cetuximab induced skin toxicity in a previously irradiated field: case report and review of the literature,” Radiation Oncology, vol. 5, no. 1, article 38, 2010.
[23]
D. G？ppner, S. Nekwasil, I. Franke, H. Gollnick, and M. Leverkus, “Successful combination therapy of a locally advanced squamous cell carcinoma of the skin with cetuximab and γ-irradiation,” JDDG - Journal of the German Society of Dermatology, vol. 8, no. 10, pp. 826–828, 2010.
[24]
U. Wollina, A. Schreiber, K. Merla, and G. Haroske, “Combined cetuximab and volumetric modulated arc-radiotherapy in advanced recurrent squamous cell carcinoma of the scalp,” Dermatology Reports, vol. 3, no. 3, article e57, 2011.
[25]
D. Giacchero, J. Barrière, K. Benezery et al., “Efficacy of cetuximab for unresectable or advanced cutaneous squamous cell carcinoma—a report of eight cases,” Clinical Oncology, vol. 23, no. 10, pp. 716–718, 2011.
[26]
M. Alter, I. Satzger, A. Mattern, A. Kapp, and R. Gutzmer, “Treatment of advanced cutaneous squamous cell carcinomas with epidermal growth factor receptor inhibitors,” Dermatology, vol. 227, no. 4, pp. 289–294, 2013.
[27]
S. J. Kalapurakal, J. Malone, K. T. Robbins, L. Buescher, J. Godwin, and K. Rao, “Cetuximab in refractory skin cancer treatment,” Journal of Cancer, vol. 3, no. 1, pp. 257–261, 2012.
[28]
K. O'Bryan, W. Sherman, G. W. Niedt et al., “An evolving paradigm for the workup and management of high-risk cutaneous squamous cell carcinoma,” Journal of the American Academy of Dermatology, vol. 69, no. 4, pp. 595.e1–602.e1, 2013.
