Medication Summary
Nonsurgical management for cutaneous squamous cell carcinoma (SCC) includes the use of systemic and topical chemotherapy. Various topical agents are used to treat patients with a history of extensive sun exposure or actinic keratosis and SCC in situ. The addition of chemotherapy to radiotherapy may also be beneficial in improving survival in squamous cell carcinoma of the head and neck but it is associated with adverse effects.
Cemiplimab, an immunotherapy, became the first systemic treatment approved for advanced cutaneous SCC. In the metastatic-disease cohort of the EMPOWER-CSCC-1 phase 2 study, 28 of 59 patients (47.5%) who received cemiplimab were seen to respond to it (median follow-up of 7.9 months). Among the responding patients, 57% had a response duration of more than 6 months. [82]
Antineoplastics, Topical
Class Summary
Nonsurgical options for the treatment of cSCC include topical chemotherapy and topical immune response modifiers. The use of topical therapy and photodynamic therapies is generally limited to actinic keratoses and in situ lesions.
Fluorouracil topical (Efudex, Carac, Fluoroplex)
5-Fluorouracil (5-FU) is a classic antimetabolite anticancer drug with a chemical structure similar to endogenous intermediates or building blocks of DNA or RNA synthesis. This agent inhibits tumor cell growth through at least 3 different mechanisms that ultimately disrupt DNA synthesis or cellular viability. Topical 5-FU is approved for the treatment of multiple actinic or solar keratoses.
PD-1/PD-L1 Inhibitors
Class Summary
Monoclonal antibody that targets checkpoint inhibitor PD-1 (programmed death 1) and blocks its interaction with programmed death ligands 1 and 2 (PD-L1 and PD-L2). This releases the PD-1 pathway-mediated inhibition of the immune response, including antitumor immune response, thereby decreasing tumor growth.
Cemiplimab (Libtayo)
Binds the PD-1 ligands PD-L1 and PD-L2 to the PD-1 receptor found on T cells, thereby inhibiting T-cell proliferation and cytokine production. It is indicated for metastatic cSCC or locally advanced cSCC in patients who are not candidates for curative surgery or curative radiation.
Pembrolizumab (Keytruda)
Monoclonal antibody to programmed cell death-1 protein (PD-1). Pembrolizumab blocks interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is indicated for the treatment of patients with recurrent or metastatic cSCC that is incurable via surgery or radiation.
Antineoplastics, EGFR Inhibitor
Class Summary
Multiple chemotherapeutic agents have been used to treat metastatic cSCC. Adaptation of traditional chemotherapeutics to local and regional administration techniques in treating head and neck cancers is being actively pursued to provide higher local concentrations of otherwise systemically toxic drugs.
Cetuximab (Erbitux)
Cetuximab is approved for the initial treatment of locally or regionally advanced SCC of the head and neck. Cetuximab when used alone is indicated for the treatment of recurrent or metastatic cases for which prior platinum-based therapy has failed. It is a chimeric immunoglobulin G1 monoclonal antibody that inhibits EGFRs and has been reported as successful in several case reports.
EGFR inhibitors are well tolerated, with relatively low risks, so they may be considered in cases not amenable to surgery or radiation or as an adjuvant in cases that pose a high risk of death. Current recommendations are to use cetuximab as an alternative to chemotherapy in patients who cannot tolerate chemotherapy.
Antineoplastics, Alkylating
Class Summary
Cisplatin is another chemotherapeutic drug of choice for metastatic cSCC. Although this agent is one of the most successful in the treatment of cancer, it produces major toxicities to normal cells and organs at the concentrations necessary for effective treatment of malignancies.
Cisplatin (Platinol, Platinol AQ, CDDP)
Cisplatin is a platinum coordination compound that inhibits DNA synthesis, cross-links and denatures strands of DNA, and disrupts DNA function by covalently binding to DNA bases. It can also produce DNA intrastrand cross-linking and breakage. It has been used in the treatment of SCC of the head and neck.
Combination chemoradiotherapy using cisplatin and concurrent radiation treatment has improved locoregional control in locally advanced SCC. Chemoradiotherapy is now considered the standard of care in locally advanced disease following surgical resection, as well as in unresectable disease. Cisplatin-based combination chemotherapy with 5-FU, methotrexate, bleomycin, and doxorubicin all have been used to treat advanced SCC, with variable outcomes.
Carboplatin (Paraplatin)
Carboplatin is an analogue of cisplatin. This is a heavy-metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA cross-links and inhibition of DNA replication. Carboplatin binds to protein and other compounds containing the SH group. It has been used in the treatment of advanced and recurrent head and neck SCC.
Antineoplastics, Antimicrotubular
Class Summary
Antimicrotubular therapy may be used as part of combination therapy in patients with SCC.
Docetaxel (Taxotere)
Docetaxel is a semisynthetic taxane, a class of drugs that inhibits cancer cell growth by promoting assembly and blocking the disassembly of microtubules, thereby preventing cancer cell division and causing cell death. It is indicated in combination with cisplatin and 5-FU for induction therapy of locally advanced SCC of the head and neck before patients undergo chemoradiotherapy and surgery.
Paclitaxel
Paclitaxel is an antimicrotubule agent. Its mechanism of action includes tubulin polymerization and microtubule stabilization, which, in turn, inhibit mitosis and may result in breakage of chromosomes. It is used off-label in SCC of the head and neck.
Antineoplastics, Antibiotic
Class Summary
Bleomycin is used as palliative treatment of head and neck SCC.
Bleomycin
Bleomycin is a cytotoxic glycopeptide antibiotic whose main mechanism of action may include inhibition of DNA synthesis and possible inhibition of ribonucleic acid (RNA) and protein synthesis.
Antineoplastics, Antimetabolite
Class Summary
Antimetabolite therapy may be used as part of combination therapy in patients with SCC.
Methotrexate (Trexall)
Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction in malignant cells. It has been used in combination with other chemotherapeutic agents for the treatment of cancers of the head and neck.
Topical Skin Products
Class Summary
The use of topical and photodynamic therapies is generally limited to actinic keratoses and in situ lesions.
Imiquimod (Aldara, Zyclara)
Imiquimod is approved by the FDA for the treatment of genital warts, actinic keratoses, and superficial basal cell carcinoma (BCC). This agent is an imidazoquinoline that enhances cell-mediated immune responses via the induction of proinflammatory cytokines; that is, it up-regulates interferon and other cytokines.
Diclofenac topical (Solaraze)
Diclofenac gel is approved by the FDA for the treatment of actinic keratoses. It is applied to lesion areas twice a day for 60-90 days.
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Large, sun-induced squamous cell carcinoma (SCC) on the forehead/temple. Image courtesy of Glenn Goldman, MD.
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Preauricular and helical scars (black arrows) from prior excisions are noted in a patient who presented with cervical metastases (white arrow) from an occult cutaneous squamous cell carcinoma.
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Contrast-enhanced, axial computed tomography (CT) scan of a patient with soft tissue invasion of the right parotid gland (arrow) by an ulcerative cutaneous squamous cell carcinoma.
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Large, neglected cutaneous squamous cell carcinoma of the right ear that requires wide local excision via auriculectomy and reconstruction. The risk of lymph node metastasis with this deeply ulcerative tumor is high enough to warrant elective neck dissection.
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Squamous cell carcinoma in situ (Bowen disease). Courtesy of Hon Pak, MD.
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Extensive conjunctival squamous cell carcinoma of the left eye. The patient had limbal and corneal involvement temporally, as well as scleral invasion with intraocular spread. A malignant cellular reaction in the anterior chamber was present. The patient was treated with a lid-sparing exenteration.
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A 35-year-old man with human immunodeficiency virus (HIV) infection presented with a 2-year history of a slowly enlarging, left lower eyelid lesion; incisional biopsy revealed squamous cell carcinoma.
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Axial magnetic resonance image (MRI) of a large squamous cell carcinoma of the left lower eyelid with invasion of the anterior orbit.
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A large, ulcerated, invasive squamous cell carcinoma of the left lower eyelid. This patient also had perineural invasion of the infraorbital nerve extending into the cranial base.
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Progressively severe atypia. The epithelium to the left is close to normal, but the epithelium to the right shows full-thickness atypia (ie, carcinoma in situ). This image illustrates carcinogenesis, the process whereby cells exposed to a carcinogen become cancerous over time.
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Squamous cell carcinoma. The lesion closely approximates the specimen in the previous image. Field cancerization is illustrated; that is, if >1 cell is exposed to a carcinogen, >1 cell becomes cancerous. Note the marked inflammatory-cell response. Should limited biopsy reveal only severe atypia with a severe inflammatory response, the lesion should be investigated further, because a cancer is likely nearby.
Tables
Stage |
Primary Tumor |
Regional Lymph Nodes |
Distant Metastasis |
Stage 0 |
Tis |
N0 |
M0 |
Stage I |
T1 |
N0 |
M0 |
Stage II |
T2 |
N0 |
M0 |
Stage III |
T3 |
N0 |
M0 |
T1-3 |
N1 |
M0 |
|
Stage IV |
T4 |
N0 |
M0 |
Any T |
N2-3 |
M0 |
|
Any T |
Any N |
M1 |
