Navigating Cutaneous Squamous Cell Carcinoma: Epidemiological Trends, Treatment Strategies, and Collaborative Care Approaches

INTRODUCTION TO NONMELANOMA SKIN CANCERS

Skin malignancies are the most common cancers in the United States.¹ Typically, skin cancer is categorized as either melanoma or non­melanoma skin cancer, which is also known as keratinocyte carcinoma (KC). The most common types of KC are basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC).^2,3

Most skin cancers are KCs, which are curable with surgical resection when detected and treated early; however, they are still associated with significant morbidity.^1,4 In contrast, melanoma accounts for about 1% of skin cancers and the most deaths.¹ Cases of KC are not reported to national registries, yet the number of Americans treated for any type of skin cancer rose from approximately 3.4 million to 4.9 million from 2002-2006 to 2007-2011.^1,5 Another estimate from 2012 suggested that the annual incidence of KCs was over 5.4 million cases that affected 3.3 million people.⁴

Given the rising incidence, KCs are associated with a significant financial burden on the US health system. Annual spending for all treatment for KCs was $6.7 billion (2024 US$) per year between 2007 and 2011.⁵ More recently, the estimated annual spending on KCs between 2016 and 2018 was $8.2 billion (2024 US$).⁶

EPIDEMIOLOGY OF cSCC

Historically, BCC was more common than cSCC; however, this has changed over time. In an analysis from 1994, the estimated lifetime risk of BCC was 28% to 33% and of cSCC was 7% to 11%.⁷ In 2012, a report from South Florida announced more cSCC cases (72%) than BCC cases (28%).⁸ In Minnesota, the incidence of BCC increased by 145% from 1976-1984 to 2000-2010, whereas the incidence of cSCC increased by 263% over the same time frames.⁹ Rogers and colleagues reported that in 2015, Medicare beneficiaries in the United States were treated for BCC as frequently as they were treated for cSCC.⁴ BCC remains a major public health concern, but current reports suggest that the incidence of cSCC is rising. As such, this paper will focus on collaborative care approaches and treatment strategies for cSCC.

Most skin cancers are caused by excessive exposure to UV radiation.^1,10 Other risk factors include immunosuppression, radiation exposure, human papillomavirus infection, increased age, and male sex.¹⁰ UV radiation from the sun causes a direct mutation in DNA base pairs within keratinocytes. The keratinocytes have a large mutational burden, yet enough of these mutations lead to the proliferation of malignant cells and KC.^10,11 Primary immunodeficiencies, use of immuno­suppressants, and immune-mediated conditions may interfere with normal immune system surveillance and regulation of damaged cells.¹⁰

Metastasis develops in 1.9% to 2.6% of patients with cSCC, and the risk of developing recurrent cSCC ranges from 13% to 31%.^12-15 Risk factors for metastases or recurrence include Breslow thickness exceeding 2 mm, invasion beyond subcutaneous fat, presence of perineural invasion, diameter exceeding 20 mm, location on the temple, and poor differentiation.¹⁶

CURRENT TREATMENT MODALITIES FOR cSCC

The current treatment of cSCC depends on risk stratification based on factors including location, size, and pathologic findings.^17,18 The NCCN defines very high–risk cSCC as any lesion larger than 4 cm or that has poor differentiation, desmoplastic histology, thickness of more than 6 mm, invasion beyond subcutaneous fat, or perineural, lymphatic, or vascular involvement.^17,18 Treatment options for patients with low-risk cSCC include surgical removal or radiation therapy (RT) for those declining surgery.¹⁷ Surgical resection is also recommended for high-risk patients for whom surgery or RT has a high likelihood of cure.

Surgery

Surgical options include curettage and electro­desiccation (C&E), shave removal, standard excision, and peripheral and deep en face margin assessment (PDEMA). Patients with low-risk disease may be treated with such minimally invasive outpatient options as C&E, shave removal, and standard excision.¹⁷ For very high–risk cSCC, however, PDEMA procedures such as Mohs surgery are preferred. These procedures are more complicated and require complete visualization of the marginal boundary, location mapping of residual tumor, and additional resection as needed to ensure negative margins.¹⁹ A systematic review and meta-analysis confirmed that the rate of recurrence after complete margin assessment was 4.08% vs 14.83% for other surgical techniques (risk ratio, 0.28; 95% CI, 0.23-0.34; P = .001).¹⁹

Multidisciplinary Care

Low- or high-risk cSCC can be controlled with local excision, but locally advanced or metastatic disease should be managed by a multidisciplinary care team and include systemic treatment or RT as indicated.¹⁷ The American Society for Radiation Oncology guidelines for definitive and postoperative RT for BCC and cSCC recommend definitive RT as a curative measure for patients with BCC and cSCC who decline or cannot undergo surgical resection.²⁰ RT is also recommended for BCC and cSCC in a location where surgery would compromise function or cosmesis. Adjuvant RT is also recommended after surgery for patients with perineural spread that is clinically or radiologically apparent, close or positive margins, recurrent cSCC after a prior negative margin resection, and regional lymph node involvement. RT is not recommended for patients with genetic conditions that predispose them to heightened radiosensitivity.²⁰

For patients with very high–risk disease, NCCN guidelines recommend systemic therapy plus RT for select cases of locally advanced or unresectable disease; resected high-risk head and neck disease; unresectable, inoperable, incompletely resected disease; regional recurrence; or distant metastatic disease. Chemotherapy options for use with RT include cisplatin, carboplatin with or without paclitaxel, and cetuximab; data to support the efficacy of these therapies, however, are limited.¹⁷

Cisplatin-based chemotherapy was originally evaluated in 28 patients with BCC or cSCC who experienced failure of surgery or RT or for whom surgery or RT was contraindicated.²¹ The overall response rate (ORR) for chemotherapy alone was 68% (complete response [CR], 28%; partial response, 40%).²¹ The data for carboplatin and paclitaxel used in combination with RT is extrapolated from studies of SCC of the head and neck.^17,22,23 A retrospective review of 150 patients with locally advanced SCC of the head and neck who received concurrent carboplatin, paclitaxel, and RT found a 3-year disease-free survival of 78.8% (95% CI, 71.8%-86.5%).²³ Another retrospective review involved 23 patients with newly diagnosed, locally advanced head and neck cancer who were deemed ineligible to receive cisplatin and were given carboplatin and paclitaxel in combination with RT; a median event-free survival (EFS) of 30 months and median overall survival (OS) of 28 months were reported.²² Both studies of carbo­platin, paclitaxel, and RT reported common toxicities including mucositis, dermatitis, taste changes, and dysphasia.^22,23

Cetuximab is also recommended in this setting based on the results of a phase 2 trial of 20 patients with advanced SCC.²⁴ Five patients were given cetuximab as first-line therapy in combination with RT, 9 patients for whom RT already failed were given cetuximab in combination with carboplatin, and 6 patients for whom RT and carboplatin were contraindicated were given cetuximab monotherapy. An ORR of 47% was observed after 9 weeks; the response was higher in those given cetuximab with RT (80%) than in those given cetuximab alone (33%) or with carboplatin (37.5%).²⁴ These regimens have demonstrated value in combination with RT; however, systemic therapy that is effective when used alone is needed for patients who decline or are not candidates for RT or surgery.

Immunotherapy for cSCC

Monotherapy with cemiplimab or pembrolizumab is recommended by the NCCN guidelines in patients with locally advanced, recurrent, or metastatic cSCC for whom curative RT or surgery is not feasible.¹⁷

Cemiplimab, the first medication for cSCC approved by the FDA, is a monoclonal antibody that targets PD-1.²⁵ It is approved for use in patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or RT.²⁶ By inhibiting PD-1, cemiplimab and other immune checkpoint inhibitors (ICIs) remove the inhibitory signals on T cells and allow the immune system to recognize and kill tumor cells.²⁶ The original trial supporting the FDA approval combined the phase 1 expansion cohort of patients with locally advanced cSCC who were not eligible for surgical resection and the phase 2 trial of patients with locally advanced or metastatic disease.²⁷ To be eligible, patients needed an ECOG performance status of 0 to 1 and adequate organ function. Patients were excluded if they had a history of autoimmune disease, solid organ transplant, prior ICI therapy, or other concurrent cancer. The phase 1 expansion cohort (NCT02383212) included 26 patients, and the metastatic disease cohort of the phase 2 study (NCT02760498) included 59 patients. All patients received weight-based cemiplimab, 3 mg/kg, every 2 weeks for up to 48 to 96 weeks or until unacceptable toxicity or disease progression occurred. The ORR of the phase 1 cohort was 50% (95% CI, 30%-70%) with a median time to response of 2.3 months (range, 1.7-7.3 months). Similarly, in the metastatic disease cohort of the phase 2 trial, the ORR was 47% (95% CI, 34%-61%) with a median time to response of 1.9 months.²⁷

In 2020, Rischin and colleagues reported results when fixed doses of cemiplimab, 350 mg, were given intravenously to patients with metastatic cSCC every 3 weeks for up to 54 to 96 weeks.²⁸ Among 56 patients included in this analysis, an ORR of 41.1% (95% CI, 28.1%-55%) and a median time to response of 2.1 months (range, 2-8.3 months) were reported. In 2024, the final analysis of all groups in the phase 2 study was published; this analysis involved data on 59 patients who received weight-based dosing for metastatic cSCC (group 1), 78 patients who received weight-based dosing for locally advanced cSCC (group 2), 56 patients who received fixed dosing for metastatic cSCC (group 3), and 167 patients who received fixed dosing for either locally advanced disease or metastatic cSCC (group 6).²⁹ The median progression-free survival (PFS) for patients receiving weight-based dosing was 18.4 months in those with metastatic cSCC and 18.5 months in those with locally advanced disease. The median OS was 57.7 months for metastatic cSCC; it was not reached for those with locally advanced disease who received weight-based dosing. For patients in group 3 who were treated with fixed dosing for metastatic cSCC, the median PFS and OS were 21.7 and 48.4 months, respectively. The primary analysis for group 6 showed a similar ORR at 44.8% and a median PFS of 14.7 months, but data for the OS analysis remain immature.²⁹ Considering these data, the prescribing information for cemiplimab recommends the fixed-dosing schedule of 350 mg every 3 weeks until disease progression or unacceptable toxicity occurs or for up to 24 months as monotherapy for advanced cSCC.²⁶

Pembrolizumab is another PD-1 targeted monoclonal antibody that was approved by the FDA in 2020 for use in patients with recurrent or metastatic cSCC or locally advanced disease that is not curable by surgery or RT based on results of the KEYNOTE-629 trial.^30-32 This open-label, single-arm, phase 2 trial involved adults with confirmed metastatic cSCC or locally advanced or recurrent disease.³² To be included, patients needed an ECOG score of 0 to 1 and had to be ineligible for surgical resection and to have undergone or be deemed ineligible for RT. Patients could also have locoregionally recurrent disease not curable by surgery or RT or have distant metastatic disease. In all, 159 patients were enrolled (locally advanced disease, 54 patients; recurrent or metastatic disease, 105 patients). They received pembrolizumab, 200 mg, every 3 weeks for up to 35 cycles or until disease progression, unacceptable toxicity, consent withdrawal, or death occurred or therapy stopped at investigator discretion. For those with locally advanced disease, the ORR was 50% (95% CI, 36%.1-63.9%); among those with recurrent or metastatic disease, the ORR was 35.2% (95% CI, 26.2%-45.2%).For the entire cohort, the median time to response was 2 months (inter­quartile ratio, 1.4-3.3 months), and the median duration of response was not reached (NR) (95% CI, 23.3 months to NR). The median PFS was 7.8 months (95% CI, 5.3-12.3 months), and the OS was 26.4 months (95% CI, 19.5 months to NR).³²

EMERGING THERAPIES AND ONGOING RESEARCH

Given the success seen with the immune ICIs cemiplimab and pembrolizumab, investigators of ongoing clinical trials are examining other ways to harness the immune system and target advanced cSCC.^29,32 Cemiplimab was evaluated in the neoadjuvant setting in a phase 2 trial (NCT04154943) involving patients with resectable stage II, III, or IV (M0) cSCC.³³ Forty of the 79 patients (56%) included had a pathological CR after treatment with neoadjuvant cemiplimab.³³ The RAMPART study (NCT05574101) is evaluating the use of cemiplimab given before, concurrently with, and following RT for advanced cSCC.³⁴ Another study (NCT06568172) involves the use of cemiplimab before, concurrently with, and following surgery in resectable stage III or IV cSCC.³⁵ C-POST (NCT03969004) is a phase 3 study evaluating adjuvant cemiplimab versus placebo after surgery or RT for high-risk cSCC.³⁶

Pembrolizumab is being given in combination with V940, an individualized neoantigen therapy, as neoadjuvant and adjuvant treatment of locally resectable, advanced cSCC (NCT06295809).³⁷ Similarly, neoadjuvant pembrolizumab is being given for resectable, locally advanced cSCC in the phase 2 DESQUAMATE study (NCT05025813).³⁸ Finally, in the phase 3 KEYNOTE-630 trial (NCT03833167), pembrolizumab is being given following surgery and RT in participants with locally advanced cSCC.³⁹

Nivolumab and nivolumab with ipilimumab given before surgery have also been studied in patients with advanced cSCC in the MATISSE trial (NCT04620200).⁴⁰ Novel immune targets such as T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains and CD155 also are being evaluated.⁴¹

MULTIDISCIPLINARY COLLABORATION IN cSCC CARE

Patients with complex disease highlight the need for multi­disciplinary collaboration in managing cSCC.¹⁷ Patients with advanced cSCC may benefit from surgery, RT, and systemic therapy involving a partnership between dermatologists, radiation oncologists, and medical oncologists.¹⁷ Consensus recommendations from an expert steering committee of the Expert Cutaneous Squamous Cell Carcinoma Leadership program also recommend that such a multidisciplinary team work together to treat patients with locally advanced or metastatic cSCC.⁴² The goal of this team should be to help patients weigh risks and benefits for all treatment modalities; while considering the patient’s preferences, the patient’s physician should present the team’s recommendations to the patient.⁴² To optimize this collaboration, other specialists in the region should be identified to determine the best communication methods to use, develop a streamlined referral process, and identify and overcome potential barriers to complex treatment.⁴³

CONCLUSION

Despite recent advances and ongoing clinical trials, cSCC remains a significant public health burden. Given various treatment options and the complicated management of advanced disease, multi­disciplinary collaborative care is imperative to successfully manage cSCC. Optimization of surgical techniques, immunotherapy, and collaboration across specialties to best treat patients with cSCC remains the goal.

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