Version October 2024
INTRODUCTION — Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin are together referred to as non-melanoma skin cancer (NMSC). NMSCs are the most commonly diagnosed malignant neoplasms among non-Hispanic White American individuals. However, reliable statistics are difficult to obtain because many patients are treated in the outpatient setting. The National Cancer Institute estimates that approximately three million new cases of NMSC were diagnosed in 2012 [1].
Despite their high prevalence, these NMSCs are rarely fatal, as they account for less than 0.1 percent of all patient deaths caused by cancer [1]. SCCs are biologically more aggressive, and neglected lesions can be life-threatening due to local extension or metastasis [2]. By contrast, BCC is only very rarely life-threatening.
In the overwhelming majority of cases, patients with NMSCs can be successfully managed with a variety of simple procedures (eg, cryotherapy, curettage and electrodesiccation, topical and intralesional treatments, or simple surgical excision). When lesions are more advanced, other local therapeutic approaches (eg, Mohs micrographic surgery, more extensive surgical resection or radiation therapy [RT]) can be used to control locoregional disease. The use of systemic therapy is limited to patients with distant metastases or locally advanced disease that cannot be adequately managed with surgery or RT.
Systemic treatments option for BCC and SCC of the skin that are not amenable to local therapies are discussed here. The diagnosis and treatment of localized basal cell and squamous cell carcinomas is discussed separately.
●Basal cell carcinoma
•(See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis".)
•(See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence".)
•(See "Treatment of basal cell carcinomas at high risk for recurrence".)
●Cutaneous squamous cell carcinoma
•(See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".)
•(See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)".)
•(See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)
TNM STAGING SYSTEM — A tumor, node, metastasis (TNM) staging system has been developed for classification of patients with advanced cutaneous squamous cell, basal cell, and adnexal carcinomas (except Merkel cell carcinoma) arising in the head and neck (table 1). This TNM system is supported by both the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) [3]. Advanced skin cancers arising at other sites are not staged using this system.
BASAL CELL CARCINOMA — For patients with advanced BCCs not amenable to local therapies such as surgery or radiation therapy (RT), options for systemic therapy include:
●Hedgehog pathway inhibitors (vismodegib, sonidegib) (see 'Initial therapy (hedgehog pathway inhibitors)' below)
●Checkpoint inhibitor immunotherapy (cemiplimab) (see 'Cemiplimab' below)
●Chemotherapy (carboplatin plus paclitaxel) (see 'Chemotherapy' below)
●Antifungal agents (itraconazole) (see 'Itraconazole' below)
Given the rarity of these tumors, patients should be encouraged to enroll in clinical trials, where available, at any time during treatment to help further determine the appropriate sequencing of these agents (algorithm 1).
Initial therapy (hedgehog pathway inhibitors) — For patients with metastatic or locally advanced BCC not amenable to treatment with surgery or RT, we suggest initial therapy with an inhibitor of the sonic hedgehog pathway rather than other available agents (algorithm 1). Options include vismodegib or sonidegib, and further data directly comparing these agents are necessary. (See 'Locally advanced disease' below and 'Metastatic disease' below.)
The hedgehog signaling pathway can cause basal cell proliferation and tumor growth [4]. Signaling in this pathway is initiated by the cell surface receptor smoothened homolog (SMO). In adults, this pathway normally is inhibited by another cell surface receptor, the patched homolog 1 (PTCH1). Binding of the hedgehog ligand to PTCH1 prevents this inhibition.
Two mechanisms have been identified by which the hedgehog pathway is involved in the pathogenesis of BCC. Mutations of PTCH1 may prevent inhibition of SMO activation of the hedgehog pathway [5,6], or mutations of SMO may result in constitutive activation of the pathway [7]. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)", section on 'PTCH protein function'.)
Two oral small-molecule inhibitors of SMO (ie, hedgehog pathway inhibitors), vismodegib and sonidegib, have clinical activity in patients with locally advanced or metastatic BCC.
Locally advanced disease — For patients with locally advanced BCC not amenable to treatment with surgery or RT, we suggest initial therapy with an inhibitor of the sonic hedgehog pathway. Options include vismodegib or sonidegib. Either agent is a reasonable option since they have not been directly compared in clinical trials, and observational data suggest higher response rates for these agents than other therapies (eg, chemotherapy, immunotherapy). (See 'Vismodegib' below and 'Sonidegib' below.)
Vismodegib — Vismodegib, a hedgehog pathway inhibitor, has clinical activity in patients with locally advanced BCC [8,9], with objective response rates between approximately 40 to 70 percent in this patient population [10-15]. For patients with locally advanced periocular BCC, vismodegib can also be used in the neoadjuvant setting to reduce tumor burden and allow surgical preservation of the eye [15-17].
Vismodegib is administered orally at 150 mg daily on a continuous dosing schedule. However, appropriate alternatives exist for those who are unable to tolerate continuous dosing, such as intermittent dosing or treatment discontinuation (with the option to reinitiate therapy at the time of relapse). (See 'Alternative dosing strategies for vismodegib' below.)
Vismodegib was evaluated in an open-label, phase II trial (the SafeTy Events in VIsmodEgib [STEVIE] study) of 1215 patients with BCC, including 1119 patients with locally advanced disease and 96 with metastatic disease. Patients were treated with vismodegib at 150 mg daily continuously until disease progression or unacceptable toxicity [10]. At a median follow-up of 18 months, among the 1119 patients with locally advanced disease, the objective response rate for vismodegib was 69 percent (95% CI 66-71 percent), including complete and partial response rates of 33 and 35 percent, respectively. Median progression-free survival (PFS) was 23 months in those with locally advanced disease and 22 months in the entire study population. Further data on the efficacy of vismodegib in patients with metastatic BCC in this study are discussed below. (See 'Metastatic disease' below.)
Treatment-associated adverse events lead to discontinuation of therapy in approximately one-third of patients. Grade ≥3 treatment-related toxicities included muscle spasms (7 percent), elevated serum creatinine phosphokinase (CPK) levels (2 percent), dysgeusia (5 percent), weight loss (4 percent), alopecia, decreased appetite, and asthenia (3 percent each), and cutaneous SCC (1 percent). Severe, life-threatening cutaneous adverse reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), have also been reported with vismodegib. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
Patients receiving vismodegib should undergo regular skin surveillance to evaluate for both response and, potentially, treatment resistance. Patients with advanced BCC can develop acquired resistance to vismodegib (ie, the tumor responds to treatment but then regrows). In one study, acquired resistance was observed in 21 percent of patients and occurred at a mean time of approximately 56 weeks [18]. Other studies have also reported primary resistance of BCC to vismodegib [19,20].
Patients receiving vismodegib should also be monitored for new skin lesions, including cutaneous SCC. The relationship between vismodegib and the subsequent development of cutaneous SCC is unclear; some observational studies suggest an increased incidence of cutaneous SCC with the use of vismodegib [21], while others found no such association [22].
Vismodegib has regulatory approved from the US Food and Drug Administration (FDA) for both metastatic and locally advanced BCC not amenable to locoregional therapy [23]. Vismodegib has also been evaluated in patients with Gorlin syndrome. (See 'Metastatic disease' below and 'Gorlin syndrome' below.)
Sonidegib — Sonidegib, another hedgehog pathway inhibitor, is a reasonable alternative to vismodegib in patients with locally advanced BCC, as data suggest comparable response rates [24]. In a meta-analysis of studies evaluating vismodegib and sonidegib, among patients with locally advanced disease, the objective response rate was similar for vismodegib and sonidegib (62 versus 55 percent) [24].
Sonidegib is administered orally at a dose of 200 mg daily, which was similarly efficacious and less toxic than a higher dose in a randomized trial [25-27]. Based on data from a phase I study [28], sonidegib was evaluated in a randomized phase II trial (BOLT) of 230 patients with BCC, including 193 patients with locally advanced and 37 with metastatic disease. Patients were randomly assigned to sonidegib at either 200 or 800 mg daily, with treatment continued until progressive disease or toxicity [25-27].
At 30 months follow-up, among patients with locally advanced disease, the objective response rates for those receiving the 200 and 800 mg doses were 56 and 45 percent, respectively [27]. The complete response rate for those receiving the 200 mg dose was 21 percent, using BCC-RECIST-like criteria. Tumor responses were durable; for those receiving the 200 and 800 mg doses, median duration of response was 24 and 26 months, respectively. Median PFS was 22 months, regardless of dose.
Grade ≥3 toxicities occurred less frequently in patients treated with 200 mg versus 800 mg (43 versus 65 percent) and included muscle spasms (11 versus 32 percent), alopecia (13 versus 23 percent), dysgeusia (13 versus 19 percent), and nausea (12 versus 16 percent).
Sonidegib has regulatory approval from the FDA for patients with locally advanced BCC who are not candidates for or who have recurred following surgery or RT [29]. However, sonidegib does not have regulatory approval from the FDA for patients with metastatic disease. (See 'Metastatic disease' below.)
Metastatic disease — For patients with metastatic disease, we suggest vismodegib over other systemic agents (algorithm 1). Available limited data suggested higher response rates for vismodegib compared with sonidegib [24] and other agents in this patient population. Additionally, sonidegib only has regulatory approval in the United States for patients with locally advanced disease not amenable to local therapies; it does not have regulatory approval for those with metastatic disease.
Vismodegib — In the phase II trial (STEVIE) described above, 1215 patients (1119 with locally advanced disease and 96 with metastatic BCC) were treated continuously with vismodegib until progression [10]. At a median follow-up of 18 months, among those with metastatic disease, the objective response rate was 37 percent, including complete and partial response rates of 5 and 32 percent, respectively. Median PFS was 13 months in those with metastatic disease and 22 months for the entire study population. The toxicity and efficacy of vismodegib in patients with locally advanced disease are discussed above. (See 'Vismodegib' above.)
Is there a role for sonidegib in metastatic basal cell carcinoma? — There is no established role for sonidegib in patients with metastatic BCC. Sonidegib has been evaluated in patients with metastatic disease in a phase II trial. However, it is not our preferred therapy in this patient population, and it does not have regulatory approval from the FDA in this population. Data are as follows:
●In a meta-analysis of studies evaluating vismodegib and sonidegib, among patients with metastatic disease, vismodegib demonstrated a higher response rate than sonidegib (39 versus 15 percent) [24].
●A randomized phase II trial (BOLT) evaluated sonidegib at 200 mg and 800 mg daily doses in 230 patients with BCC, including 193 patients with locally advanced and 37 with metastatic disease. For those with metastatic disease, the objective response rates were 8 and 17 percent, respectively, in the 200 and 800 mg dose groups.
Further results of the BOLT trial in those with locally advanced disease are discussed separately. (See 'Sonidegib' above.)
Alternative dosing strategies for vismodegib — Treatment-related toxicity leads to discontinuation in approximately one-third of patients receiving vismodegib [30-32]. There is no standard approach to intermittent therapy; options include administering vismodegib at 150 mg daily in three-month intervals alternating with two-month treatment breaks, or at 150 mg every other day. (See 'Intermittent therapy' below.)
Additionally, for patients who achieve a complete response on vismodegib and are intolerant of therapy, an alternative approach includes discontinuing treatment, with the option of reinitiating therapy at the time of relapse. Retreatment schedules may also depend on toxicity resolution, as well as patient willingness to restart therapy. (See 'Treatment discontinuation after a complete response' below.)
These alternative dosing strategies have not been evaluated using sonidegib, and further data on its dosing are discussed separately. (See 'Sonidegib' above.)
Intermittent therapy — Despite the promising efficacy of hedgehog pathway inhibitors, concerns regarding the high rates of treatment discontinuation due to toxicity have led to interest in intermittent courses of vismodegib. This approach is based on a randomized study investigating the use of two different schedules of administration, which were both associated with high response rates; however, the criteria for response were different than those used in the STEVIE trial [32].
In a placebo-controlled phase II trial (MIKIE), 229 patients with multiple advanced BCCs were randomly assigned to one of two intermittent dosing schedules of vismodegib for a total of 72 weeks (18 months). The first group received vismodegib at 150 mg daily in three-month intervals, alternating with placebo at two-month intervals, whereas the second group received vismodegib at 150 mg daily for an initial six-month interval, followed by alternating two-month intervals of placebo and vismodegib [32]. Both schedules demonstrated a similar reduction in the mean total number of BCCs at the end of treatment relative to baseline (63 versus 54 percent, respectively) and comparable toxicity profiles.
Treatment discontinuation after a complete response — Treatment discontinuation is another strategy that has been explored to address the toxicities of continuous treatment. For example, in patients with a complete response to vismodegib, treatment discontinuation can still result in sustained responses, with a high response rate upon vismodegib re-exposure for relapsed disease [30].
In one observational study, 116 patients with locally advanced BCC who experienced a complete response to vismodegib stopped therapy at a median of approximately eight months and were placed on clinical observation [30]. In these patients, three-year relapse-free survival was 36 percent. Among the 27 patients who relapsed and were rechallenged with vismodegib, 23 patients had an objective response (85 percent), 10 of whom had a complete response (37 percent). Additionally, other studies using a similar approach have suggested lower rates of grade ≥3 adverse events (29 to 36 percent) compared with continuous administration (43 percent) [30-32].
Ineligible for hedgehog pathway inhibitors — For patients who do not have access to or are intolerant of initial therapy with hedgehog pathway inhibitors (eg, musculoskeletal toxicities, weight loss, or decreased Eastern Cooperative Oncology Group (ECOG) performance status (table 2) unrelated to disease), we alternatively offer checkpoint inhibitor immunotherapy with the programmed cell death 1 (PD-1) inhibitor cemiplimab. Further data on this agent are discussed separately. (See 'Cemiplimab' below.)
Subsequent therapy
Treatment approach — We offer checkpoint inhibitor immunotherapy with the PD-1 inhibitor cemiplimab for patients with locally advanced or metastatic BCCs who are not eligible for further curative locoregional therapy (eg, surgery or RT) and who have progressed on or are intolerant of a hedgehog pathway inhibitor (algorithm 1). Cemiplimab offers the potential for prolonged treatment responses and is well tolerated in this patient population.
For patients who decline or who are ineligible for immunotherapy, we offer alternative therapies (eg, chemotherapy or itraconazole) or enrollment on clinical trials, where available. (See 'Less preferred alternatives' below.)
Cemiplimab — The efficacy of cemiplimab was evaluated in an open-label nonrandomized trial (Study 1620) of 84 patients with locally advanced, unresectable and 54 patients with metastatic BCC who experienced disease progression, were intolerant of, or lacked an objective response after nine months on hedgehog pathway inhibitor therapy [33,34]. The study excluded patients who were candidates for further locoregional therapy (eg, surgery or RT); those with autoimmune disease requiring immunosuppressive agents within five years; those who had undergone solid organ transplantation; those previously treated with checkpoint inhibitor immunotherapy; and those with HIV, or hepatitis B or C infection.
Patients received cemiplimab for up to 93 weeks, or until disease progression or unacceptable toxicity. Objective response rates were assessed using radiographic imaging and digital photography evaluation of the target lesion (if visible). Results were as follows:
●Locally advanced basal cell carcinoma – Among the 84 patients with locally advanced BCC, objective responses were seen in 26 patients (31 percent), including 5 complete (6 percent) and 21 partial (25 percent) responses [33]. A majority (79 percent) of patients maintained durable responses lasting six months or longer.
●Metastatic basal cell carcinoma – Among the 54 patients with metastatic BCC, objective responses per investigator assessment were seen in 14 patients (26 percent) including 2 complete responses (4 percent) and 12 partial responses (22 percent) [34]. The median progression-free survival was 10 months and overall survival 50 months. The median duration of response was not reached.
Common grade ≥3 toxicities in both cohorts include hypertension (5 percent), fatigue (4 percent), musculoskeletal pain, decreased appetite, headache, urinary tract infection (2 percent each), and rash, nausea, constipation, and anemia (less than 1 percent each) [33].
Based on these data, the FDA granted approval for cemiplimab in patients with locally advanced or metastatic BCC previously treated with or in those who are not appropriate for a hedgehog pathway inhibitor [35]. Further data are necessary to confirm the efficacy of cemiplimab in this population, including tumor response rate and durability of response.
Less preferred alternatives — Systemic agents such as systemic chemotherapy or itraconazole are available for patients who have progressed on or who are ineligible for treatment with immunotherapy. However, these are less preferred options, as available data suggest limited response rates for these agents. Enrollment in clinical trials is encouraged, where available.
Chemotherapy — Chemotherapy with the combination of carboplatin and paclitaxel may have efficacy in treatment-refractory metastatic BCCs, with complete responses observed in some patients [36-38]. Because of the rarity of metastatic BCC, the approach to systemic treatment is based primarily upon observational case reports. As an example, a case report of one patient with BCC metastatic to the lungs observed a complete response with a combination of carboplatin and paclitaxel [36]. In a literature review, 12 other patients with metastatic BCC were treated with platinum-containing regimens [36]. Among these 12 patients, 5 had a complete response and 4 had a partial response. (See 'Alternative chemotherapy agents' below.)
Itraconazole — Itraconazole, an antifungal agent, has been identified as a potent inhibitor of the hedgehog signaling pathway. While itraconazole has limited efficacy in patients with treatment-refractory BCC, it is a well-tolerated treatment option that can be administered orally [39]. Additionally, itraconazole can be used in resource-limited settings where hedgehog pathway inhibitors, immunotherapy, or chemotherapy may not be readily available.
In one observational study, itraconazole was evaluated in 19 patients, with an average of 4.8 cutaneous BCCs per patient [40]. In one cohort, 15 patients were treated with a dose of 200 mg twice daily for four weeks prior to surgery; in the other cohort, four patients received a dose of 100 mg twice daily for one to four months (mean 2.3 months). Eight patients had tumor reduction and re-epithelialization. Of note, none of the three patients previously treated with vismodegib responded.
CUTANEOUS SQUAMOUS CELL CARCINOMA — Patients with cutaneous SCC not initially amenable to locoregional therapy with surgery or radiation therapy (RT) are treated using systemic therapy. The role of immunotherapy followed by surgery in patients with locally advanced, cutaneous SCC is evolving. Treatment decisions should be made with multidisciplinary input from surgical oncology, medical oncology, and radiation oncology. Our approach is based upon the resectability of the tumor.
Options for systemic therapy include:
●Checkpoint inhibitor immunotherapy (cemiplimab, pembrolizumab)
●Chemotherapy (carboplatin plus paclitaxel, single-agent chemotherapy)
●Epidermal growth factor receptor (EGFR) inhibitors (cetuximab)
Patients with resectable disease — We offer neoadjuvant immunotherapy only to those in whom upfront surgery would cause significant morbidity. Data demonstrate that neoadjuvant immunotherapy can induce a pathologic complete response (pCR) in approximately one-half of patients with resectable disease, especially those with cutaneous disease of the head and neck [41,42]. It may also reduce tumor burden and allow for surgical preservation of structures adjacent to the primary tumor, such as the eye. However, it remains unclear whether it improves survival outcomes, and therefore we do not offer it to all patients. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)" and "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)
When a neoadjuvant approach is chosen, we suggest immunotherapy with cemiplimab followed by surgery, as this approach has high pathologic response rates and can reduce surgical morbidity (eg, orbital sparing). Patients with a complete (or near complete) clinical response may alternatively continue immunotherapy along with active surveillance of the tumor rather than proceeding to surgery, which may be reserved for relapsed disease. The addition of RT to immunotherapy is an appropriate alternative to surgery for certain cases, such as tumor involving the deep lobes of the parotid gland or directly on the skull.
For patients receiving neoadjuvant immunotherapy followed by surgery, we offer up to four cycles of neoadjuvant cemiplimab, depending upon treatment response and tolerance. Surgery typically follows within five weeks of completing immunotherapy (although it can be performed sooner if there are no medical or surgical contraindications). In select cases, additional cycles may be given prior to surgery to achieve a point of maximal treatment response.
For patients with locoregional lymph node involvement that responds to immunotherapy, some UpToDate contributors offer surgical resection of the lymph nodes as well as the primary tumor. However, immunotherapy may result in pseudoprogression of locoregional lymph nodes alone, an immunotherapy-induced phenomenon where disease transiently worsens prior to stabilization or response. When examination or imaging suggests progression in the lymph nodes only, some contributors offer a biopsy to distinguish pseudoprogression from true progression. Those with pseudoprogression may be eligible for resection, whereas those with true progression are not. Alternatively, other contributors offer up to two additional cycles of immunotherapy with repeat imaging (to reassess whether the pseudoprogression evolves into either a treatment response or true disease progression) rather than lymph node biopsy, which may be difficult to interpret pathologically for pseudoprogression. (See "Principles of cancer immunotherapy", section on 'Immunotherapy response criteria'.)
Data supporting neoadjuvant therapy come from a nonrandomized phase II study, in which 79 patients with locally advanced stage II, III, or IV (M0) (table 1) cutaneous SCC who were eligible for surgical resection were treated with up to four cycles of neoadjuvant cemiplimab followed by surgery [42]. Surgery was performed within 11 to 36 days after completing neoadjuvant therapy. After neoadjuvant therapy, 54 patients (68 percent) experienced an objective responses by imaging, and pCR was seen in 40 patients (51 percent) [42,43]. At median follow-up of 19 months, there were no recurrences in patients who achieved a pCR. Neoadjuvant cemiplimab was well tolerated (grade ≥3 toxicity in 18 percent of patients during the neoadjuvant period and 25 percent in the 16 patients who completed up to a year of adjuvant therapy). Most patients had advanced disease (stage III or IV [M0] (table 1)) in the head and neck region, and some were spared more extensive, disfiguring surgery such as orbital exenteration. While further randomized trials may determine if the addition of neoadjuvant immunotherapy to surgery in the setting of localized disease improves disease-free or overall survival, these data suggest an excellent response to immunotherapy alone. We await long term outcomes prior to offering this approach in all patients with resectable disease, reserving it for those in whom upfront surgery would cause significant morbidity.
Patients with unresectable disease
Eligible for immunotherapy — For most patients with locoregionally advanced or metastatic SCC who are not eligible for curative treatment with surgery or RT and are eligible for immunotherapy, we suggest the use of a programmed cell death 1 (PD-1) inhibitor rather than chemotherapy, cetuximab, or their combination (algorithm 2). Options include cemiplimab, pembrolizumab, and nivolumab which are all effective and less toxic than other available systemic agents. Therefore, any of these agents are a reasonable option, as they have not been directly compared in randomized clinical trials. (See 'Cemiplimab' below and 'Pembrolizumab' below and 'Nivolumab' below.)
Cemiplimab — Cemiplimab and other immunotherapy agents may be offered to patients with SCC secondary to immunosuppression from hematologic malignancies (eg, chronic lymphocytic leukemia) or from systemic treatment of these disorders, after a risk-benefit discussion with the clinician. Although data are limited for this approach, UpToDate contributors have safely and effectively treated these patients with immunotherapy in clinical practice. (See 'Pembrolizumab' below.)
We do not offer cemiplimab or other immunotherapy agents to patients with SCC secondary to immunosuppression related to allogeneic organ transplantation. These patients were excluded from trials evaluating cemiplimab due to concerns regarding organ rejection and graft-versus-host disease (in the case of hematopoietic cell transplantation) [44]. (See 'Allogenic organ transplantation' below.)
Cemiplimab has activity in patients with locally advanced or metastatic cutaneous SCC (table 1). Data are as follows:
●Locoregionally advanced or metastatic disease – The most extensive data on the efficacy of cemiplimab come from a phase I expansion cohort and an open-label phase II trial of patients with unresectable, locally advanced disease or distant metastases who had been previously treated with systemic therapy or RT [44]. The trials excluded patients who had undergone transplantation, those with autoimmune disease treated with immunosuppressive therapy any time in the previous five years, and those with hematologic malignancies (such as chronic lymphocytic leukemia).
In the phase I study, objective responses were seen in 13 of 26 patients (50 percent). In the phase II study, objective responses were observed in 35 of 75 patients with metastatic disease (47 percent) and in 6 of 10 patients with unresectable, locally advanced disease (60 percent). With a median follow-up of eight months in the phase II cohort, approximately one-half of the responding patients with metastatic disease continued to have durable disease control at the time of data cutoff. Treatment was well tolerated, with no single grade ≥3 toxicity present in more than 5 percent of patients, including pneumonitis (3 percent) and diarrhea (2 percent). (See "Toxicities associated with immune checkpoint inhibitors".)
●Locally advanced disease without nodal or distant metastases – In further follow-up of a separate cohort in the phase II study reported above, 78 patients with locally advanced cutaneous SCC without nodal disease or distant metastases who were not eligible for RT or surgery were treated with cemiplimab for up to eight months [45]. At a median follow-up of approximately nine months, objective responses were seen in 34 patients (44 percent), including 10 complete responses (13 percent) and 24 partial responses (31 percent). There were no new unexpected toxicities.
Based on these data, cemiplimab is approved by the US Food and Drug Administration (FDA) for treatment of patients with advanced cutaneous SCC who are not candidates for curative surgery or RT. The use of immunotherapy in patients with autoimmune disease is discussed separately. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Pre-existing autoimmune disease'.)
Pembrolizumab — The PD-1 inhibitor pembrolizumab is an effective and well-tolerated option for patients with advanced and metastatic cutaneous SCC. (See 'Cemiplimab' above.)
Pembrolizumab was evaluated in an open-label, nonrandomized phase II trial (KEYNOTE-629) of 159 patients with advanced and metastatic cutaneous SCC. The study included 54 patients with locally advanced, unresectable disease (with approximately 22 percent receiving prior systemic therapy, mostly platinum-based chemotherapy with radiation [46]) and 105 patients with locally advanced recurrent or metastatic disease (with a majority receiving one or more prior systemic therapies [87 percent] or RT [74 percent] [47]). Patients received pembrolizumab at 200 mg intravenously every three weeks until disease progression, unacceptable toxicity, or a maximum of two years. Patients with autoimmune disease or those requiring immunosuppressive therapy were excluded from the trial. Data for each of the subgroups are as follows:
●Locally advanced, unresectable disease – At median follow-up of 15 months, the objective response rate was 50 percent, with complete and partial response rates of 17 and 33 percent, respectively [46]. One-year progression-free survival (PFS) and overall survival (OS) rates were 54 and 74 percent, respectively. Among the 27 patients with disease response, 10 (37 percent) experienced durable responses lasting 12 months or longer.
●Recurrent or metastatic disease – In those with locally advanced recurrent or metastatic disease, at median follow-up of 27 months, the objective response rate was 35 percent, with complete and partial response rates of 10 and 25 percent, respectively [46,47]. One-year PFS and OS were 36 and 61 percent, respectively. Among the 37 patients with disease response, 25 (68 percent) experienced durable responses lasting 12 months or longer.
In all patients, treatment- and immune-related grade ≥3 toxicity rates were 12 and 8 percent, respectively; no new toxicity profiles for pembrolizumab were noted in this study [46].
In a separate phase II study (CARSKIN) enrolling treatment-naïve patients only (n = 39), median PFS and OS were 7 and 25 months, respectively [48]. In an expansion cohort that included an additional 18 patients, the objective response rate with pembrolizumab was 42 percent, with higher rates among those with programmed cell death ligand 1 (PD-L1)-positive disease (55 percent) versus PD-L1-negative disease (17 percent).
Pembrolizumab is approved by the FDA for treatment of patients with recurrent or metastatic cutaneous SCC or locally advanced cutaneous SCC that is not curable by surgery or RT [49]. The dosing of pembrolizumab in patients with SCC and other approved indications is discussed separately.
Nivolumab — The PD-1 inhibitor nivolumab is an effective and well-tolerated option for patients with advanced and metastatic cutaneous SCC.
In an open-label phase II trial, 24 patients with metastatic and/or locally advanced cutaneous SCC received nivolumab at 3 mg/kg every two weeks until disease progression, unacceptable toxicity, or one year of treatment [50]. At median follow-up of 18 months, objective responses were seen in 14 patients (58 percent), which were all partial responses; the median duration of response was not reached. Median PFS and OS were 13 and 21 months, respectively. Nivolumab was well tolerated in this study which included older adults.
Immunotherapy followed by surgery, in select patients — Among patients with localized unresectable disease treated with PD-1 inhibitor immunotherapy (eg, cemiplimab or pembrolizumab), approximately two-thirds have ongoing partial responses at follow-up [45,47,51]. For select patients with unresectable tumors that are subsequently rendered resectable with immunotherapy (either cemiplimab, pembrolizumab, or nivolumab), we suggest surgical resection either at the point of maximal treatment response to immunotherapy or at the point of initial conversion to resectable disease. (See 'Patients with resectable disease' above.)
However, since data are limited for this approach, alternatives to surgery include continuing treatment with immunotherapy, either alone or with the addition of RT.
Ineligible for immunotherapy — Patients with advanced or metastatic SCC who are ineligible for checkpoint inhibitor immunotherapy may alternatively be offered systemic chemotherapy, using an approach similar to those who have progressed on immunotherapy. (See 'Subsequent therapy' below.)
Subsequent therapy — The optimal treatment approach to patients with advanced cutaneous SCC who have progressed on initial therapy is not established. Our approach is to use either systemic chemotherapy or EGFR inhibitors such as cetuximab. Observational data are inconclusive for the most effective subsequent-line treatment options [52-55], and randomized studies with large numbers of patients are limited. Patient enrollment in clinical trials are encouraged. The choice of therapy is based on clinical factors including age, performance status, comorbidities, prior therapies, as well as the response rates and toxicities of the chosen therapies.
Carboplatin plus paclitaxel — For patients who have progressed on or are ineligible for immunotherapy, we suggest subsequent treatment with carboplatin plus paclitaxel rather than other available systemic agents (algorithm 2). However, older adults or those who are unable to tolerate the potential toxicities of carboplatin plus paclitaxel may alternatively be offered single-agent cetuximab or other chemotherapy agents. (See 'Alternative chemotherapy agents' below.)
As an example, in one retrospective observational study of 87 patients with advanced cutaneous squamous cell carcinoma, approximately one-quarter (27 percent) received carboplatin plus paclitaxel, the frequently used initial therapy [53]. In the entire study population, the response rates for those with locally advanced and metastatic disease were 18 and 19 percent, and median OS was 16 and 15 months, respectively.
Cetuximab — Cetuximab, a monoclonal antibody that targets EGFR, has antitumor activity in patients with advanced SCC of the skin (picture 1). Data for cetuximab are as follows:
●Advanced or metastatic disease – In a phase II study of 36 patients with locoregional or metastatic disease, cetuximab was administered weekly as a single agent (400 mg/m2 on week 1 and then 250 mg/m2 weekly) [56]. In the entire study population, the objective response rate was 28 percent, including eight partial and two complete responses. Three patients were able to undergo complete resection of their tumor following treatment with cetuximab. Patients developing acneiform rash demonstrated longer PFS (five versus two months) and OS (nine versus four months). The most common grade ≥3 toxicities included infection and tumor bleeding.
Cetuximab has also been combined with platinum-based chemotherapy (including cisplatin [55], carboplatin [57], or carboplatin plus paclitaxel [58]) in patients with unresectable, advanced, nonmetastatic cutaneous SCC, but data are limited for this approach.
●Is there a role for surgery after cetuximab? – For patients with locally advanced unresectable disease, including older adults, cetuximab may be used to reduce tumor burden and allow for subsequent tumor resection. In another observational study, 34 patients with initially unresectable, locally advanced disease were treated with cetuximab, either in combination with platinum and fluorouracil or as a single agent if chemotherapy was considered contraindicated [59]. Among the nine patients treated with cetuximab alone, five had a response that allowed for surgical resection, and three of these had a complete pathological response. Among the 25 patients (with a median age of 70 years) treated with cetuximab and chemotherapy, 23 patients were able to have surgery, and a complete pathological response was achieved in 15 tumors.
Alternative chemotherapy agents — There are limited data for the efficacy of other systemic chemotherapy agents in the treatment of advanced cutaneous SCC. Cisplatin either as a single agent or in combination with other agents such as fluorouracil with or without bleomycin [52,60,61] or anthracyclines [62] are efficacious, and their use has been extrapolated from those used for SCC arising in other noncutaneous sites. However, patients with advanced cutaneous SCC are often older adults or those with significant comorbidities who may be unable to tolerate the toxicities associated with cisplatin-based combinations. Other available non-cisplatin chemotherapy options include single-agent carboplatin, topical fluorouracil, capecitabine [52,63], and methotrexate [64]. (See "Systemic chemotherapy for cancer in older adults".)
As an example, a combination of bolus cisplatin, plus a five-day infusion of bleomycin and fluorouracil, was used to treat 14 patients with advanced SCC of the skin or lip [60]. Objective tumor responses (four complete and seven partial) were observed in 11 patients, including complete and partial responses in four and seven patients, respectively. Among seven patients, tumor regression with systemic chemotherapy permitted subsequent definitive local treatment with either surgery or RT.
The efficacy of systemic chemotherapy administered concurrently with radiation in high risk, aggressive cutaneous SCC are discussed separately. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Radiation therapy'.)
Investigational therapies — The use of other EGFR tyrosine kinase inhibitors such as panitumumab [65,66], gefitinib [67], and erlotinib [68] remain investigational, as data suggest limited activity for these agents.
SPECIAL CONSIDERATIONS
Gorlin syndrome — Vismodegib may also have a role in patients with nevoid BCC syndrome (ie, Gorlin syndrome), an inherited condition in which patients develop multiple BCCs that are histologically identical to sporadic lesions [69]. Since patients with nevoid BCC syndrome develop multiple BCCs in their 20s and 30s, the potential teratogenic effects of vismodegib are very important in this group. Vismodegib should only be given to women of childbearing age using adequate methods of birth control for at least one month prior to initiation of and during treatment with vismodegib. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)
Allogenic organ transplantation — We do not routinely use immune checkpoint inhibitors (ICI) in patients who have received an organ transplant due to limited data in this population and the risk of rejection of the transplanted organ. Our treatment of these patients is individualized and considers the type of organ transplant, comorbidities, and immunosuppression.
The immunosuppression required after allogenic organ transplantation increases the risk of various skin cancers. In this setting, SCC is more common than BCC, in contrast with the distribution of skin cancers in the nontransplant population. SCCs and BCCs that arise in this setting are more aggressive and are more likely to recur after resection. The development of skin cancer in patients with chronic immunosuppression following organ transplantation is discussed separately. (See "Malignancy after solid organ transplantation", section on 'Skin cancers'.)
Skin cancers that develop in this population may respond to reductions or modifications to the immunosuppressive regimen. This is discussed in detail separately. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Choice and modulation of immunosuppressive regimen'.)
●Kidney transplant – A decision about starting ICI in patients with a kidney transplant must carefully weigh the potential benefit to ICI, alternatives to ICI, and risk for loss of the transplanted kidney. While limited data suggests activity of ICI in this population, there is a risk of organ rejection.
A phase I study in 12 patients with kidney transplants and advanced cutaneous squamous cell carcinoma treated with cemiplimab demonstrated a response in 46 percent of evaluable patients with 18 percent having a durable response over a year [70]. All patients received a daily mechanistic target of rapamycin (mTOR) inhibitor and pulsed dose corticosteroids (for a total of seven days with each cycle). At a median followup of seven months, no kidney rejection was seen.
On the other hand, in a different trial patients with kidney transplants who have cutaneous squamous cell (five patients), Merkel cell carcinoma (two patients), and melanoma (one patient) who were treated with nivolumab, tacrolimus, and prednisone had no objective response [71]. However, two out of six patients who progressed on nivolumab had a complete response when ipilimumab was added to nivolumab, tacrolimus, and prednisone. Unfortunately, two out of six patients who received ipilimumab (one with a complete response and one with progressive disease) had a treatment-related allograft loss.
●Other organs – We do not offer ICI to patients who developed advanced SCC of the skin in non-kidney transplants. It is not clear that these agents are active in this immunosuppressed population and there is a risk of organ rejection. Such patients were excluded from randomized trials evaluating immunotherapy due to concerns regarding organ rejection and graft-versus-host disease (in the case of hematopoietic cell transplantation) [44]. Although an early phase clinical trial [72], and some observational studies [73-75], suggest that immunotherapy may be safe and effective in this population, other studies suggest an allograft rejection rate of 39 percent in liver transplant and 20 percent in heart transplant [74]. Further data in this area are necessary.
For these patients, the choice of cetuximab, chemotherapy, or their combination (extrapolating from data in SCCs of the head and neck) should take into account patients' preferences, end-organ function, and performance status. For example, in the rare case of the patient with aggressive disease with visceral involvement, combination chemotherapy with cetuximab may be offered as an attempt at controlling the disease. However, there are increased toxicities associated with this approach, and some chemotherapy agents (eg, cisplatin) may not be appropriate if agents to prevent rejection are being administered that are also associated with kidney toxicity. (See "Treatment of metastatic and recurrent head and neck cancer", section on 'Active agents' and "Nephrotoxicity of chemotherapy and other cytotoxic agents", section on 'Cisplatin' and 'Cemiplimab' above.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Non-melanoma skin cancer (The Basics)")
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nonmelanoma skin cancer".)
SUMMARY AND RECOMMENDATIONS
●Locoregional therapy for cutaneous squamous and basal cell carcinomas – Cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) are the most common malignancy among non-Hispanic White American individuals. In the overwhelming majority of cases, locoregional therapy is curative, and systemic therapy is not indicated. (See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence" and "Treatment of basal cell carcinomas at high risk for recurrence" and "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)".)
●Initial therapy for basal cell carcinomas – For patients with metastatic or locally advanced BCC that is not amenable to treatment with surgery or radiation therapy (RT), our approach is as follows (algorithm 1) (see 'Initial therapy (hedgehog pathway inhibitors)' above):
•Locally advanced disease – For patients with locally advanced disease, we suggest either vismodegib or sonidegib rather than other available agents (Grade 2C). Either agent is a reasonable option since they have not been directly compared in clinical trials, and observational data suggest higher response rates for these agents than other therapies (eg, chemotherapy, immunotherapy). (See 'Locally advanced disease' above and 'Vismodegib' above and 'Sonidegib' above.)
•Metastatic disease – For patients with metastatic disease, we suggest vismodegib over other systemic agents (Grade 2C), as available limited data suggest a higher response rate for vismodegib compared with sonidegib and other therapies. (See 'Metastatic disease' above.)
•Indications for intermittent dosing of vismodegib – For patients who are unable to tolerate the toxicities of continuous dosing of vismodegib, we administer treatment using an intermittent dosing schedule. For those who achieve a complete response to therapy and are intolerant of therapy, we discontinue vismodegib, with the option of reinitiating therapy at relapse. Retreatment schedules may also depend on toxicity resolution, as well as patient willingness to restart therapy. (See 'Alternative dosing strategies for vismodegib' above.)
●Subsequent therapy for basal cell carcinomas – For patients with locally advanced or metastatic BCCs who have progressed on, are intolerant of, or are without access to a hedgehog pathway inhibitor, we suggest checkpoint inhibitor immunotherapy with the programmed cell death 1 (PD-1) inhibitor cemiplimab rather than other systemic agents (Grade 2C). (See 'Subsequent therapy' above and 'Cemiplimab' above.)
●Immunotherapy-refractory basal cell carcinomas – For patients who progress on or who are ineligible for immunotherapy, we offer alternative agents (eg, chemotherapy with carboplatin plus paclitaxel, itraconazole) or enrollment in clinical trials, where available. Based on limited data, complete responses have been observed with carboplatin and paclitaxel, whereas itraconazole is well tolerated, administered orally, and can be used in resource-limited settings where other agents are not readily available. (See 'Less preferred alternatives' above.)
●Initial therapy for cutaneous squamous cell carcinomas – For most patients with metastatic or locally advanced SCC that is not amenable to treatment with surgery or RT, we suggest the use of a PD-1 inhibitor (Grade 2C) rather than chemotherapy, cetuximab, or their combination (algorithm 2). Options include cemiplimab, pembrolizumab, or nivolumab in this setting; any of these agents are a reasonable option, as they have not been directly compared in randomized clinical trials. (See 'Eligible for immunotherapy' above and 'Cemiplimab' above and 'Pembrolizumab' above and 'Nivolumab' above.)
•Squamous cell carcinoma due to hematologic malignancies – Cemiplimab and other immunotherapy agents may be offered to patients with SCC secondary to immunosuppression from hematologic malignancies (eg, chronic lymphocytic leukemia) or from systemic treatment of these disorders, after a risk-benefit discussion with the clinician. Although data are limited for this approach, UpToDate contributors have safely and effectively treated these patients with immunotherapy in clinical practice. (See 'Cemiplimab' above.)
•Patients with organ transplantation – We do not offer immune checkpoint inhibitors (ICI) to most patients who develop advanced SCC of the skin following transplant due to limited data in this population and risk of organ rejection. For these patients, the choice of cetuximab, chemotherapy, or their combination (extrapolating from data in SCCs of the head and neck) should consider patients' preferences, end-organ function, and performance status.
Patients with kidney transplants may be candidates for ICI based on limited data which suggests efficacy, but must carefully weigh the alternatives to ICI and potential for loss of the transplanted organ. (See 'Allogenic organ transplantation' above.)
●Surgical resection of cutaneous squamous cell carcinoma after immunotherapy – The role of immunotherapy followed by surgical resection in locally advanced cutaneous squamous cell carcinoma is evolving, and multidisciplinary input is necessary. (See 'Immunotherapy followed by surgery, in select patients' above.)
•Unresectable disease – For select patients with unresectable tumors that are subsequently rendered resectable with immunotherapy (either cemiplimab, pembrolizumab, or nivolumab), we suggest surgical resection (Grade 2C), either at the point of maximal treatment response to immunotherapy, or at the point of initial conversion to resectable disease. Alternatives to surgery include continued treatment with immunotherapy, either alone or with the addition of radiation therapy (RT).
•Resectable disease – For those with resectable disease without significant risk of morbidity, we proceed directly to surgery.
For patients with resectable tumors at risk for significant morbidity or disfigurement, we suggest neoadjuvant cemiplimab followed by surgery rather than surgery alone (Grade 2C), given decreased surgical morbidity and high pathologic response rates, especially in those with cutaneous disease of the head and neck. However, the impact on overall survival is unknown. (See 'Immunotherapy followed by surgery, in select patients' above.)
-For most patients, we offer up to four cycles of neoadjuvant cemiplimab. In select cases, additional cycles may be given prior to surgery to achieve a point of maximal treatment response.
-Patients with a complete (or near complete) clinical response may, after careful shared decision-making, continue immunotherapy with active surveillance of the tumor rather than proceeding to surgery, which may be reserved for relapsed disease.
-The addition of RT to immunotherapy is an appropriate alternative to surgery for certain cases, such as tumor involving the deep lobes of the parotid gland or directly on the skull.
●Subsequent therapy for cutaneous squamous cell carcinomas – For patients with advanced or metastatic SCC who progress on or are ineligible for immunotherapy, we suggest subsequent treatment with carboplatin plus paclitaxel rather than other available systemic agents (Grade 2C). However, older adults or those who are unable to tolerate the potential toxicities of carboplatin plus paclitaxel may alternatively be offered single-agent cetuximab or other chemotherapy agents. (See 'Subsequent therapy' above.)
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