Director, Phase I/Investigational Therapeutics

Director, Melanoma and Soft Tissue Oncology Program

Squamous cell carcinoma of the skin (SCCS) is an increasingly common diagnosis and is the second most common type of skin cancer worldwide.

 The number of cases of SCCS has increased consistently over the past 20 years. This observation may be related to improved detection of skin cancer, increased exposure to UV radiation (including tanning bed exposure), and the aging of the US population, because the incidence of SCCS increases dramatically with age.

With a 10% decrease in stratospheric ozone annually and the continued growth of the aging US population, locally advanced and metastatic squamous cancers arising from a skin primary are likely to continue to increase annually in coming years, particularly in geographic areas with significant sun exposure.

 These cancers also plague patients who are immunosuppressed, such as recipients of solid organ transplants or patients with chronic infections (eg, HIV)—populations that are living longer in recent years and are therefore becoming more likely to develop troublesome SCCS.

	Most often, SCCS and its precursor lesions are localized and amenable to resection. However, larger and more invasive lesions often require multimodality care, with 10-year survival rates dramatically impacted by the development of regional lymph node involvement and distant metastases.

	Relatively little has been done to develop a generalized management plan for these patients.

 Even the development of a widely accepted staging system has been challenging, as the current AJCC system does not easily identify high-risk cancers, with most poor outcomes occurring in stage T2 cases. While alternate staging systems have been proposed to stratify T2 tumors based on poor prognostic factors such as poor differentiation, perineural invasion, tumor diameter ≥2 cm, and invasion beyond subcutaneous fat,

 the lack of validated systems and clear guidelines leads to confusion for practitioners and variability in treatment.

	Questions persist not only about which patients should be defined as high risk, but also what the initial surgical management of high-risk patients should be, particularly the role of sentinel lymph node. There are no high-level data to guide the decision to use this staging tool, although smaller published reports indicate that a select group of patients with high-risk SCCS may benefit from sentinel lymph node biopsy to identify occult nodal metastases, with a suggested cutoff threshold of 10% risk.

 The need to conduct further clinical trials in this area has been identified.

	Not surprisingly, there is also a lack of high-level data on treatment options for SCCS not amenable to resection. Published case reports have demonstrated responses to platinum-based chemotherapy with occasional complete responses.

There are no data from prospective phase III studies available, and only one prospective phase II study examining the use of platinum-based chemotherapy in this population has been reported. Cisplatin, either as a single agent or combined with 5-FU, has occasionally produced meaningful responses, but again, data supporting efficacy is limited. In general, extrapolation of regimens from squamous tumors of the head and neck are employed, despite the fact that these tumors are likely to be biologically distinct. Further investigation is limited by a lack of available trials for SCCS, and by the frequent exclusion of SCCS patients from trials for head and neck cancer patients.

	Because the EGFR is highly expressed in many epithelial tumors, including SCCS,

and EGFR-directed therapy is often a component of treatment for squamous tumors of the head and neck, the use of anti-EGFR therapies for SCCS is increasing. The largest prospective study to date by Maubec et al

 examined the EGFR inhibitor cetuximab. They enrolled 36 poor-prognosis SCCS patients whose tumors expressed EGFR and demonstrated a disease control rate of 69%.

	A smaller, 16-patient study of the EGFR inhibitor panitumumab in patients who received prior local and/or systemic treatment showed antitumor activity with a response rate of 31%, including 3 partial responses and 2 complete responses.

	Furthermore, a trial evaluating the neoadjuvant use of the EGFR tyrosine kinase inhibitor gefinitib enrolled 22 evaluable patients and demonstrated a 18.2% complete and 27.3% partial response rate and did not interfere with subsequent local therapy, indicating antitumor activity worthy of further exploration.

 Due to their availability as FDA-approved agents, and the lack of competing attractive therapeutic options, cetuximab or panitumumab are increasingly employed to treat locally advanced or metastatic SCCS, and EGFR inhibition is now part of NCCN guidelines for treatment of advanced disease. While this may be a useful therapeutic approach, if these patients are not enrolled as part of rigorous randomized studies, practice-changing information cannot be gathered, and many important questions will remain unanswered.

	For example, could preoperative systemic and/ or radiation therapy reduce the morbidity and extent of the subsequent surgical procedure? Does combining chemotherapy with EGFR inhibitors improve clinical outcomes and increase the pathologic complete response rate? In this era of personalized medicine, are there genomic predictors of response and resistance? Finally, is there a role for immunotherapy in this disease? These are questions we routinely ask in other malignancies; the time has come to include SCCS in these investigations.

	In summary, advanced SCCS continues to be a treatment challenge given the aggressive behavior of a subset of cases and the absence of randomized clinical trials to provide guidelines for therapy. Multidisciplinary clinical trials and collaborative efforts are necessary to advance the care of this growing patient population.

				Alam M and Ratner D. Cutaneous squamous-cell carcinoma. 

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				Gaffney DC, Soyer HP, Simpson F. The epidermal growth factor receptor in squamous cell carcinoma: an emerging drug target. 

				Schmults CD, Karia PS, Carter JB, et al. Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study. 

				Navarrete-Dechent C, Veness MJ, Droppelmann N, Uribe P. Highrisk cutaneous squamous cell carcinoma and the emerging role of sentinel lymph node biopsy: literature review.” 

				Lawson JD, Otto K, Chen A, et al. Concurrent platinum-based chemotherapy and simultaneous modulated accelerated radiation therapy for locally advanced squamous cell carcinoma of the tongue base. 

				Nakamura K, Okuyama R, Saida T, Uhara H. Platinum and anthracycline therapy for advanced cutaneous squamous cell carcinoma. 

				DeConti RC. Chemotherapy of squamous cell carcinoma of the skin. 

				Maubec E, Petrow P, Scheer-Senyarich I, et al. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. 

				Foote MC, McGrath M, Guminski A, et al. Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma. 

				Lewis CM, Glisson BS, Feng L, et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. 

Articles

Advanced SCCS continues to be a treatment challenge given the aggressive behavior of a subset of cases and the absence of randomized clinical trials to provide guidelines for therapy.

James S. Goydos, MD

Articles

Advanced Squamous Carcinoma of the Skin: A Persistent, Growing Challenge