Introduction

Squamous cell carcinoma (SCC) is the second most common skin cancer and accounts for 20% of all cutaneous malignancies, or 1 million cases in the USA each year [1]. SCC is the most commonly diagnosed skin cancer in darker skin types and is more likely to present at a more advanced stage [2, 3]. Risk factors for developing cutaneous SCC (cSCC) include advanced age, chronic exposure to ultraviolet radiation (UVR), UVR-sensitive skin, X-ray radiation, chemical exposure (e.g., arsenic or polycyclic hydrocarbons), and immunosuppression [4]. Invasive cSCC is defined histologically as the presence of infiltrative cells passing through the basement membrane into the dermis [5]. Surgical excision is the treatment of choice for invasive cSCC and is greater than 95% curative [4, 6]. In a limited number of cases, where surgery may not be possible, other options include topical therapies or destructive therapies such as radiotherapy, cryotherapy, curettage and electrodessication, or photodynamic therapy [4].

A minority of patients with invasive cSCC may be incurable due to metastasis or local progression unamenable to surgery or radiation therapy [7••]. These patients are considered to have advanced cSCC and palliative systemic therapy should be considered [7••]. Though only 5% of cSCCs become locally advanced, recur, or metastasize, the fatality rate is 1–5% (about 9000 deaths annually in the United States) for this subset of patients [8•, 9]. The presence of metastasis provides a poor prognosis with a median survival of less than 2 years, with one study showing an 89% mortality rate at 5 years for distant metastases [4]. This article discusses new treatments for advanced cSCC and whether a new definition for the disease entity should be considered, using a previously proposed definition for advanced basal cell carcinoma (BCC) for comparison.

Programmed Death-1 Inhibitors

Cemiplimab is a new systemic therapy that was FDA-approved in September 2018 as the first treatment for advanced cSCC [10]. Cemiplimab is a human monoclonal antibody that targets PD-1 with high affinity and high potency [11]. PD-1 plays a role in the immune response to cancer and can be found on white blood cells such as macrophages and lymphocytes [12, 13•]. Tumor cells bind to PD-1 using programmed cell death ligand-1 (PDL-1) and programmed cell death ligand-2 (PDL-2) to prevent an immune response from being mounted [12, 13•]. Cemiplimab prevents this binding of tumor cells to PD-1 [12, 13•].

A recently published study reported results of phase I and II trials of cemiplimab in adult patients with advanced cSCC. The expansion cohort of the phase I trial included 26 patients aged 55 to 88 years (median 73) with locally advanced cSCCs that had not responded to radiation or prior systemic therapy. Participants were eligible for inclusion in the study if they were not candidates for surgery due to (a) disease recurrence after two or more surgical procedures with expectations that curative resection would be unlikely or (b) surgery was anticipated to result in substantial complications or deformities [7••]. The phase I study showed a 50% (13/26) response rate for advanced cSCCs.

The phase II trial included 59 patients aged 38–93 (median 71) with distant or regional metastases and showed a 47% (28/59) response rate for metastatic cSCC [7••]. Cemiplimab was dosed at 3 mg/kg every 2 weeks for 48 weeks and 96 weeks in phase I and II studies, respectively [7••]. Safety data was evaluated in 534 patients. The most common adverse reactions were fatigue, rash, and diarrhea. Serious adverse events, while rare, were infusion reactions and immune-mediated reactions (e.g., pneumonitis, nephritis, hepatitis, colitis, and endocrine abnormalities).

Prior Treatments

Prior to cemiplimab, treatment options for cSCC included chemotherapy with platin derivatives and EGFR inhibitors. Chemotherapy such as cisplatin or carboplatin was considered the first line for advanced cSCC but had limited clinical data [14•]. Certain criteria such as advanced age, poor overall condition, or comorbidities may disqualify chemotherapy as an option [8•]. In these cases, EGFR inhibitors could be considered such as cetuximab and panitumumab. One study of cetuximab showed disease control in 69% of patients with 2 complete remissions and 8 partial remissions [15]. Oral EGFR inhibitors are another option, such as gefitinib which has shown a complete response rate of 18.2% and a partial response rate of 27.3% when used as a neoadjuvant [16]. A key issue with EGFR inhibitors is the frequent resistance that occurs [8•]. However, as with chemotherapy, clinical data is limited to EGFR inhibitors [8•]. Despite having these treatment options, there is currently no standard for the management for advanced cSCCs [8•]. Given the poor evidence and efficacy of the aforementioned treatment options, cemiplimab is an appealing new option given that it is the first systemic medication specifically tested for cSCCs while providing an improved efficacy rate of 47–50% as compared to previously available medications [7••]. Table 1 reviews treatment options for advanced cSCC.

Table 1 Medications for advanced SCC
Full size table

Redefining Advanced cSCC

Advanced BCCs were recently redefined to address the lack of standardized criteria with the purpose of expanding the limited treatment options available for this small subset of patients [17, 18]. Redefining advanced cSCC should be considered for similar reasons. Lear et al. expanded the definition of advanced BCC to “basal cell carcinoma of American Joint Committee on Cancer (AJCC) stage II or above, in which current treatment modalities are considered potentially contraindicated by clinical or patient-driven factors.” [18] Disease factors included tumor size, location, number of tumors, subtype, and likelihood of successful treatment (e.g., recurrent BCC) while patient factors included age (e.g., radiotherapy in young patients), performance status (e.g., frail patients), quality-of-life effects (e.g., poor cosmetic outcome), patient opinion of the treatment, presence of genodermatoses (e.g., Gorlin’s syndrome), and comorbidities (e.g., organ transplant) [18]. Vismodegib was subsequently discussed in another article regarding its potential uses within this new definition of advanced BCC, both as a neoadjuvant to improve cosmetic outcome prior to surgery and as an adjuvant to decrease treatment duration and therefore minimize adverse events [17].

Similarly, advanced cSCC has not yet been redefined although it also lacks standardized criteria. Given its first FDA-approved medication (cemiplimab) was released onto the market, it would be prudent to propose a new definition to help determine which patients are amenable to this treatment. While surgery and a combination of chemotherapy and radiation therapy have been considered the gold standard, other factors such as the general condition of the patient, age, comorbidities, and immunosuppression should be considered as with advanced BCCs [19]. The definition of advanced BCC is relatively new (2014); given the rarity of advanced BCC and cSCC, as well as the recent development of hedgehog inhibitors (HHi) and PD-1 inhibitors, perhaps it was felt there was no need to define advanced disease until recently. Though the 5-year survival rates for BCCs and SCCs are comparable (10% and 11%, respectively), the more severe side effects of HHi for advanced BCC are mild (myopathies, alopecia, dysgeusia) compared to checkpoint inhibitors such as PD-1inhibitors for advanced cSCC (immune-mediated reactions) [4, 7••, 20, 21]. This stark contrast in side effects may have further contributed to a delay in, or perhaps even prevented, the broadening of criteria to diagnose advanced cSCC.

In Lear et al.’s expanded criteria of advanced BCC, they included genodermatoses such as Gorlin’s syndrome as a patient factor to consider during diagnosis [18]. Though recurrent BCCs are difficult to manage and require multiple operations, this may not be feasible in patients with genodermatoses yielding multiple lesions, and radiotherapy may be contraindicated due to a high risk of developing further BCCs [22]. Similarly, immunosuppressed patients (e.g., post-transplant/chemotherapy) can develop a multitude of cSCCs and should be considered their own category among advanced cSCCs requiring their own management. For example, multiple studies of acitretin have shown efficacy in preventing cSCC in immunocompromised post-transplant patients [23,24,25].

A broadened definition of advanced cSCC should also include lesions in the H-zone. Markowitz et al. discussed facial BCCs which may be small but not considered advanced by the old definition. Though lesions in the H-zone may be small, they are considered to be in a high-risk area though amenable to surgery. This may cause a less ideal cosmetic outcome, especially if the lesion were to be on the lip. The same principles should apply to advanced cSCC, which if on the lip might require a wedge excision otherwise. Treatment options for advanced disease were limited until HHi were introduced, and now with cemiplimab, cSCC may be treated while keeping both disease and patient factors in mind. Similar to how vismodegib has been combined with imaging to monitor lesion size prior to surgery, cemiplimab could also be used as a neoadjuvant to decrease the cosmetic impact of therapy. While PD-1 inhibitors have early immune-mediated side effects, broadening the definition of SCC can be helpful when considering other safer treatment modalities such as neoadjuvants.

Conclusions

We propose adding certain subsets of patients to the definition of advanced cSCC including immunosuppressed patients and lesions cosmetically unamenable to surgery due to location. With the introduction of cemiplimab as the first FDA-approved medication for advanced cSCC, an expansion of diagnostic criteria opens up treatment options to a broader population. Certain patients may also require different approaches such as the use of acitretin in immunosuppressed patients. As new treatments unfold for rare but fatal diseases, we should continue to re-evaluate how we diagnose and manage patients.