Cutaneous squamous cell carcinoma (CSCC) is a non-melanoma skin cancer of keratinocytic origin, and accounts for approximately 20% of all keratinocytic cancers, standing as the second most common neoplasm after basal cell carcinoma (BCC) (1). The main risk factors are chronic exposure to ultraviolet (UV) radiation, followed by age, fair phototype and immunosuppression [specifically related to solid organ transplantation (2), chronic lymphocytic leukemia (3), and HIV infection (4)] (5). Other risk factors like the exposure to arsenic and polyaromatic hydrocarbons can be considered occupational (6).

CSCC is characterized by a high tumor mutational burden (TMB) (7) with a large amount of UV radiation-related mutations, most notably C>T and CC>TT dinucleotide mutations (8). However, genetic mutations that could lead to a targeted treatment are infrequent, and may include PIK3CA, fibroblast growth factor receptor 3 (FGFR3), BRAF and EGFR (9).

Some hereditary syndromes may increase the risk of developing CSCC such as xeroderma pigmentosum, epidermolysis bullosa, oculocutaneous albinism, Lynch syndrome, and Fanconi syndrome (1).

Due to the heterogeneity of clinical and histologic presentations, therapeutic options, and low mortality rates, accurate data on the incidence and prevalence of CSCC are not available to-date. In Australia, where the highest incidence of skin cancer is generally recorded, there are an estimated 387 cases per 100,000 (10). In the United States, more than 700.000 new cases of CSCC are diagnosed annually, and about 3900-8800 people die each year due to this disease (11). In Europe, the incidence of CSCC ranges across different latitudes from 9 to 96 per 100.000 for male individuals and 5 to 68 per 100.000 for females (12–15).

In more than 90% of cases, the prognosis is good and treatment consists of minimally invasive surgical procedures or, in selected cases, other local therapy modalities (16). In case of primary CSCC for which curative surgery is not indicated, definitive radiotherapy (RT) may be considered as a primary treatment. Despite the lack of randomized trials comparing the outcomes of RT versus surgery and other local therapy modalities, in a systematic review and pooled analysis of 7 observational studies for a total of 761 primary CSCCs, the local relapse with RT was as low as 6.4% (17). However, especially in the immunocompromised patient population, in case of social difficulties, lack of caregiver support, and/or in presence of multiple comorbidities, CSCC can manifest in locally advanced or metastatic forms representing an emerging clinical problem (5). In these cases, local treatments are no longer indicated to achieve an appropriate disease control. Until few years ago, the only available therapeutic options were chemotherapy and targeted therapy (i.e., EGFR inhibitors), with poor response rates and duration of response, and frequently at the cost of unacceptable toxicities for such a frail population. With the approval by the Food And Drug Administration (FDA) and European Medicines Agency (EMA) of the anti-PD-1 cemiplimab in 2018, and of the anti-PD-1 pembrolizumab by the FDA only in 2020, immunotherapy has become the standard of care for patients with CSCC who are not eligible for curative surgery or radiotherapy (18).

In this review, we will discuss the main criteria for the identification of CSCC patients who are at high risk of relapse, and the multidisciplinary definition of locally advanced CSCC, according to the most recent guidelines. In addition to that, the results of main systemic treatment regimens will be discussed, with a focus on immunotherapy, especially regarding the key findings on the new therapeutic options and future therapeutic landscapes.

In most cases, CSCCs are detected as small or early-stage lesions that have a low risk of recurrence after an appropriate surgical treatment (16). Specifically, the overall recurrence rate has been shown in several studies to be between 2.1% and 4.6% (19). Although only few CSCC have a high risk of local or distant recurrence, it is essential to identify the high-risk patient group for a proper diagnostic and therapeutic workup, and an individualized follow-up. Risk factors can be either tumor-related (clinical or pathological) or patient-related, as indicated by the European Dermatology Forum (EDF), European Association of Dermato-Oncology (EADO), and European Organization for Research and Treatment of Cancer (EORTC) guidelines (20, 21). However, the impact of each individual risk factor is not entirely clear. In a recent meta-analysis, published data on risk factors for recurrence, metastasis, and disease-specific death of CSCC were systematically analyzed. The main results of this work were summarized in Table 1 (22). Briefly, tumor depth was associated with the highest risk ratio of local recurrence and metastasis, while a tumor diameter > 20 mm was associated with the highest risk ratio of disease-specific death (22).

There are several available staging systems for CSCC but each of them presents some important pitfalls and may not be able to fully provide an adequate risk stratification for all cases. The American Joint Committee on Cancer (AJCC) 8th edition classification does not perform well especially regarding T stage, as few tumors fit the criteria for T4, but most T2 tumors actually turn out to be associated with poor outcomes (23). Brigham and Women’s Hospital (BWH) and the Breuninger systems are more accurate in stratifying the risk of T stage but are limited to the classification of primary tumors only (24). Finally, neither the AJCC nor the BWH staging systems consider immunosuppression, which is included as a major high-risk factor in the EADO and NCCN guidelines (20, 21, 25). Indeed, immunosuppression associated with conditions such as solid organ transplantation (26), HIV infection, and chronic lymphocytic leukemia (CLL), is not only a risk factor for increased incidence of CSCC, but also a risk factor for a more unfavorable outcome (20). Therefore, further efforts are needed to develop a dedicated classification for CSCC that could be more useful in daily clinical practice for risk stratification and early identification of high-risk CSCC (20).

Advanced CSCC is defined as a tumor for which neither surgery nor radiation therapy with curative intent is indicated (21). This broad definition is driven by the fact that there is no precise consensus on when CSCC can be considered advanced (27). In addition, contraindication to surgery or radiation therapy with curative intent may be due to several reasons which include not only the anatomic extent of the tumor, but also the patient’s clinical condition, comorbidities, the risk of mutilation or severe functional loss due to the surgery, previous treatments performed, and patient preference (27).

The advanced form can be divided into locally advanced and metastatic (loco-regional and distant). Advanced forms are considered rare; it is estimated that only about 5% of total CSCC cases may become advanced, with the limitations of missing epidemiologic data (20). Unfortunately, while the definition of metastatic CSCC (mCSCC) implies the dissemination of tumor cells through locoregional lymph nodes or both distant lymph node and other visceral sites, there are no precise parameters for defining the locally advanced forms, and a multidisciplinary discussion is essential for defining the best diagnostic and therapeutic strategies. In general, a locally advanced CSCC (laCSCC) is a tumor which is no longer eligible for either surgery or curative radiation therapy due to multiple recurrences, large extension, bone erosion and/or deep infiltration beyond the subcutaneous tissue into muscles/nerve. Moreover, the definition of laCSCC could fit tumor masses where curative resection may lead to unacceptable complications, morbidity or deformity (27). Finally, multiple CSCCs related to genetic syndromes as xeroderma pigmentosum and those related to chronic conditions such as chronic lymphocytic leukemia (CLL) may be included in these criteria (27). Patient-related features, such as age, comorbidities and patient preferences, may also play a role in the choice of either surgery or immunotherapy.

The ongoing clinical studies recruiting patients with advanced or high-risk CSCC are summarized in Table 2 . In most trials a treatment regimen including a PD-1 inhibitor is being investigated, and especially in earlier settings, such as high-risk CSCC. Most significantly, in the R2810-ONC-1788 study (NCT03969004), patients with high-risk CSCC are randomized to receive cemiplimab for 1 year versus placebo after surgery and adjuvant radiation therapy. The primary endpoint is disease-free survival (DFS). Cemiplimab is also being investigated in the neoadjuvant setting. Specifically, Gross and colleagues presented at the European Society of Medical Oncology (ESMO) meeting 2019 data from a phase 2 study (NCT03565783) where 20 patients with stage III/IV (M0) (AJCC 8th edition) CSCC of the head and neck received 2 doses of preoperative cemiplimab achieving a 55% of pathological complete response (pCR) and a major pathology response (MPR) in 15% (47). There were no grade ≥ 3 adverse events (47).

Immunotherapy has led to pivotal changes in advanced CSCC both in terms of objective responses, survival, and improved quality of life. However, patients with advanced CSCC receiving immunotherapy after more than one recurrence after surgical excision had less than half the probability of achieving an objective response (43). This could be related to primary or secondary resistance to immunotherapy (48). For this reason, clinical trials are ongoing with the aim of overcoming resistance to immunotherapy. In fact, the combination of PD-1 or PD-L1 inhibitors with other agents (such as radiotherapy, oncolytic viruses, or EGFR inhibitors) is being investigated to overcome primary or secondary resistance to immunotherapy, such as in the I-Tackle trial (NCT03666325) with the addition of cetuximab to pembrolizumab at primary or acquired resistance; or in the UNSCARRed study (NCT03737721) with the addition of radiotherapy to avelumab.

Cutaneous squamous cell carcinoma is a common condition, although it remains rare in its advanced stages; high-risk cases require multidisciplinary care due to the complexity associated with both the disease and the often frail population (27). Before the introduction of immunotherapy in clinical practice, a standard of care for advanced CSCC was not clearly defined, and up to 60% of patients with advanced CSCC did not receive any systemic therapy at all, due to the low clinical activity and high risk of severe toxicities (21). Based on a strong preclinical rationale, clinical trials were conducted leading to the registration by the regulatory authorities of anti-PD-1 immunotherapy in patients with advanced CSCC (21). Cemiplimab was the first PD-1 inhibitor receiving an indication in CSCC after showing in a clinical trial rapid and durable responses in more than 40% of patients (in Figures 1 , 2 we reported two clinical cases of rapid clinical response), with a favorable safety profile. In addition to that, cemiplimab led to an improvement in health-related quality of life with a reduction in cancer-related pain after a few cycles of therapy (18, 43, 44).

Anti-PD-1 drugs are the backbone of current clinical investigation in patients with CSCC. Specifically, several clinical trials with PD-1 inhibitors are currently underway investigating the activity, efficacy, and safety of adjuvant approaches in individuals with high-risk CSCC, and neoadjuvant approaches in patients with advanced CSCC. Based on the results of these studies, anti-PD-1 drugs may soon become standard of care in the adjuvant and neoadjuvant settings.

FS and PQ jointly supervised this work. All authors contributed to the article and approved the submitted version.

FS received honoraria for presentations or lectures from Sanofi, Roche, BMS, Novartis, Merk, SunPharma, MSD, Pierre Fabre, and surved on advisory boards of Novartis, Philogen, SunPharma and MSD; PQ reports consulting or advisory role for Bristol Myers Squibb, Merck & Co., Novartis, Pierre Favre, Roche/Genentech, and Sanofi.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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