Cutaneous Squamous Cell Carcinoma Overview
by Dr. Joseph Barone, BCOP
Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) are categorized as non-melanoma skin cancers (NMSCs). NMSCs are very common types of cancer since they are more prevalent than all other types of cancers combined. A 2012 retrospective review of data from the Centers for Medicare & Medicaid Services (CMS) physician claims database indicated that approximately 5 million patients were treated for NMSCs during that particular year. Approximately 50% of those NMSC patients were found to have cSCC.1,2
Risk factors for the development of cSCC include chronic sun exposure; total site-specific sun exposure; the number of site-specific sunburns; indoor tanning bed use; increasing age; individuals with fair skin, hair, and eye color; the presence of sun-induced, pre-cancerous lesions such as actinic keratoses; certain genetic syndromes such as albinism or xeroderma pigmentosum; and certain conditions resulting in immunosuppression such as solid organ transplantation, lymphoma, chronic lymphocytic leukemia (CLL), drug-induced immunosuppression, and human immunodeficiency virus (HIV).2
Most cases of cSCC are non-metastatic (i.e. Stage I, II, or III) although they may cause substantial skin or bone destruction as well as areas of aesthetic disfigurement. Approximately 0.4% of cSCC patients will develop metastatic disease. When considering all stages of cSCC collectively, the five-year overall survival (OS) estimates exceed 90%.2,3
According to the National Comprehensive Cancer Network (NCCN) Guidelines for Squamous Cell Skin Cancer, a patient with a lesion suspicious for skin cancer should undergo a complete skin exam, regional lymph node exam, biopsy, and additional imaging studies (i.e. computerized tomography (CT)) if the presence of the extensive disease is suspected. A biopsy will determine whether the skin lesion is non-cancerous versus cancerous. If cancerous, a biopsy will further determine if the lesion is malignant melanoma or a NMSC.
Upon identification of cSCC on biopsy, the oncologist will determine the appropriate tumor staging using the American Joint Committee on Cancer (AJCC) TNM Staging Classification for Cutaneous Carcinoma of the Head and Neck. For TNM staging, T indicates the size of the primary tumor, N indicates the presence (or not) of lymph node involvement, and M indicates the presence (or not) of distant metastatic disease. Staging will determine whether the patient’s cSCC is Stage 0, I, II, III, or IV, as well as the modality of treatment used to treat the patient’s cSCC.
Treatment of Localized Cutaneous Squamous Cell Carcinoma
Localized cSCC refers to disease that has not yet spread to the lymph nodes (i.e. AJCC Stage 0, I, II, and certain Stage III). Localized cSCC treatment depends on whether the patient has a low or high risk of disease recurrence. According to the NCCN Guidelines for Squamous Cell Skin Cancer, factors that predispose cSCC patients to a high risk of disease recurrence include any of the following:
- Any lesion regardless of size involving the central face, eyelids, eyebrows, nose, lips, chin, mandible, pre-/post-auricular skin, temple, ears, genitalia, hands, or feet
- Any lesion greater than or equal to 20 millimeters involving the trunk and extremities
- Any lesion greater than or equal to 10 millimeters involving the cheeks, forehead, scalp, neck, and pretibial
- Any lesion with poorly defined borders or is poorly differentiated
- Any lesion which is rapidly growing or has recurred at a site of previous radiation therapy
- Any lesion with greater than 6 millimeters in depth or with perineural, lymphatic, or vascular involvement
- Presence of active immunosuppression or neurological symptoms
According to the NCCN guidelines for Squamous Cell Skin Cancer, localized cSCC patients with a low risk for recurrence are managed with surgical resection (i.e. curettage and electrodesiccation (C&E) or standard excision with 4- to 6-millimeter surgical margins). For patients who are not candidates for surgical resection, radiation therapy (RT) would be the most appropriate treatment option. If a standard excision results in positive surgical margins, further surgical resection via Mohs micrographic surgery, standard excision, or RT may be considered.
Localized cSCC patients with a high risk for recurrence are managed with more invasive surgical procedures such as Mohs micrographic surgery or standard excision with wider surgical margins. For patients who are not candidates for surgical resection, RT would be the most appropriate treatment option. If surgical resection results in positive surgical margins, the surgical procedures may be reattempted, or RT may be considered. If further surgical resection or RT are not feasible treatment options, systemic therapy with chemotherapy, biological agents, or immunotherapy may be considered. Systemic treatment options will be discussed in the next section.
Appropriate patient follow-up after successful treatment of localized cSCC should involve a physical exam every three to 12 months for two years, followed by every six to 12 months for three years, then annually thereafter. Patients should also be educated on appropriate protection from sun exposure as well as how to perform a self-examination of the skin.
Treatment of Locally-Advanced and Metastatic Cutaneous Squamous Cell Carcinoma
According to the NCCN Guidelines for Squamous Cell Skin Cancer, patients with locally advanced (i.e. lymph node-positive AJCC Stage III) cSCC are usually managed with surgical resection of the primary tumor in combination with regional lymph node dissection. Following this procedure, RT alone or RT in combination with systemic therapy may be considered (i.e. Cisplatin, Cisplatin + Fluorouracil, Cetuximab, or Carboplatin) to reduce risk of disease recurrence. For patients with locally advanced cSCC who are not candidates for surgical resection or RT, Cemiplimab-rwlc (Libtayo®) is considered as the NCCN-preferred therapy in this scenario. Other treatment options include Cisplatin, Cisplatin + Fluorouracil, Cetuximab, Carboplatin, or consideration for clinical trial enrollment. Platinum-based chemotherapy is listed an NCCN-category 2B recommendation due to a lack of adequate clinical trial data demonstrating efficacy.
Appropriate patient follow-up after successful treatment of locally advanced cSCC should involve a physical exam every one to three months for one year, followed by every two to four months for one year, followed by every four to six months for three years, then annually thereafter. Patients should also be educated on appropriate protection from sun exposure as well as how to perform a self-examination of the skin.
Patients with distant metastatic disease are not typically candidates for surgical resection or radiation therapy. In this scenario, the NCCN guidelines for Squamous Cell Skin Cancer recommend immunotherapy with Libtayo, an anti-PD-L1 monoclonal antibody, as the preferred treatment option. Other treatment options include Cisplatin, Cisplatin + Fluorouracil, Cetuximab, Carboplatin, or consideration for clinical trial enrollment.
In September 2018, Libtayo became the first product specifically approved by the Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic cSCC who are not candidates for curative surgical resection or RT. This approval occurred as a result of the NCT02383212 and NCT02760498 clinical trials which demonstrated that locally advanced or metastatic cSCC patients receiving Libtayo obtained a 47.2% objective response rate (ORR). Additionally, 61% of patients who responded received therapy for at least six months. Libtayo is administered as a 350 mg intravenous infusion over 30 minutes every three weeks. Libtayo is available as a 350 mg/7 mL single-dose vial (NDC 61755-008-01) and should be stored under refrigeration (2-8 degrees Celsius). The prescribing information for Libtayo contains warnings for severe and/or fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis, nephritis, endocrinopathies, and dermatological reactions, non-immune-mediated infusion reactions, and embryo-fetal toxicity. The most common adverse drug reactions for Libtayo include fatigue (29%), rash (25%), diarrhea (22%), nausea (19%), musculoskeletal pain (17%), pruritis (15%), constipation (12%), and decreased appetite (10%).4
1 Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the U.S. population, 2012. JAMA Dermatol 2015; 151:1081-1086
2 National Comprehensive Cancer Network Guidelines for Squamous Cell Skin Cancer Version 1.2020
3 Rubio-Casadevall J, Hernandez-Pujol AM, Ferreira-Santos MC, et al. Trends in incidence and survival analysis in non-melanoma skin cancer from 1994 to 2012 in Girona, Spain: A population-based study. Cancer Epidemiol 2016; 45:6-10
4 Libtayo Prescribing Information https://www.regeneron.com/sites/default/files/Libtayo_FPI.pdf