Treatment of unresectable and metastatic cutaneous squamous cell carcinoma

Abstract

Cutaneous squamous cell carcinoma (SCC) is an already common disorder with a rapidly increasing incidence. Treatment of early disease depends primarily on surgery or destructive techniques. In contrast to the frequency of early SCC, unresectable or metastatic SCC is relatively rare, but potentially life-threatening without clearly proven treatment options. Few rigorous studies of the treatment of advanced SCC have been undertaken. In the past, various agents have been explored in a limited fashion, including chemotherapy (cisplatin, fluoropyrimidines, bleomycin, doxorubicin), 13-cis-retinoic acid, and interferon-α2a. Clinical activity has been suggested by these trials, but their small sizes, heterogeneous patient populations, and lack of randomization have hindered the use of their results in defining treatment paradigms. Only one rigorous randomized trial has focused on cutaneous SCC. Enrolling 66 patients, that trial randomized patients at high recurrence risk to either observation or postoperative interferon-α2a and 13-cis-retinoic acid. This treatment did not improve time to recurrence or prevent secondary cutaneous SCC from developing. Though not in the metastatic setting, this study casts doubt on the ability of this regimen to control metastatic disease. Recently, agents targeting the human epidermal growth factor receptor (erlotinib, gefitinib, cetuximab) have displayed preliminary evidence of activity in phase II clinical trials and case series reports. Expression of this receptor is frequent in cutaneous SCC and appears to be prognostically adverse. Only the conduct of rigorous trials, with well-defined endpoints, adequate patient numbers, and preferably randomization, can prove the clinical efficacy of this promising treatment approach and define better therapy for this vexing clinical problem.

Figure 1.

Signaling pathways and effects of EGFR. Upon binding to one of multiple ligands, EGFR dimerizes with another member of the EGFR family, leading to the activation of the TK domain, phosphorylation of critical tyrosine residues in the EGFR intracellular domain, and activation of downstream signaling pathways, including MAPK, JAK-STAT, PLC, and PI3K–Akt. Collectively, EGFR signaling may lead to increased cell proliferation, decreased apoptosis, increased angiogenesis, increased invasion, and increased metastasis. As depicted above, multiple opportunities exist to inhibit EGFR signaling; for example, monoclonal antibodies (e.g., cetuximab and panitumumab) interact with the extracellular domain of EGFR preventing ligand-induced activation of the receptor, and small-molecule inhibitors (e.g., gefitinib, erlotinib, and lapatinib) block activation of the TK domain preventing induction of EGFR signaling pathways. Specific EGFR mutations may lead to constitutive activation of EGFR regardless of ligand binding and/or resistance of EGFR to the effects of TK inhibitors. Independent of receptor status, EGFR downstream signaling may become aberrantly activated; for example, mutant Ras may lead to constitutive activation of the MAPK pathway or mutation/loss of PTEN may lead to loss of negative regulation of the PI3K–Akt pathway. Abbreviations: DAG, diacylglycerol; EGFR, epidermal growth factor receptor; IP3, inositol triphosphate; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/extracellular signal–related kinase kinase; PDK, 3-phosphoinositide-dependent protein kinase; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol bisphosphate; PKC, protein kinase C; PLC, phospholipase C; PTEN, phosphatase and tensin homologue deleted on chromosome ten; STAT, signal transducer and activator of transcription; TGF, transforming growth factor; TK, tyrosine kinase.