Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

SCC in situ (Bowen disease)

1st line – destructive therapies

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ACUTE
|
SCC in situ (Bowen disease)
1st line – 

destructive therapies

Destructive therapy may include ablative laser vermilionectomy, ablative skin resurfacing, chemical peels, cryotherapy, curettage and electrodesiccation.[73]

Local destruction with liquid nitrogen (cryotherapy) is commonly applied.[99][100]​ This often results in a delayed formation of a vesicle or bulla. In patients with darker skins, cryotherapy may cause hypopigmentation in the long term.

Electrodessication and curettage is another common method but carries the risk of dyspigmentation and scarring.[101] The dermatologist curettes the clinically apparent tumor with a sharp round instrument, then coagulates the wound bed with electric current to dryness. The eschar is curetted twice more with subsequent electrodessication.

Laser therapy has been demonstrated to be an acceptable alternative to surgery for low-risk lesions on the trunk and extremities for patients with SCC.[102]

Photodynamic therapy, whereby a topical photosensitizer, such as 5-aminolevulinic acid or methyl aminolevulinic acid, induces protoporphyrin accumulation that results in cell death with exposure to visible light, is now widely used and compares well with other methods.[103]

Studies have shown that the efficacy of photodynamic therapy is similar to, or more effective than other traditional therapies, such as cryotherapy and electrodessication and curettage, with superior cosmetic outcomes.[103][104]​ Photodynamic therapy is an option for patients with tumors at sites where wound healing is poor/delayed, in the case of multiple and/or large tumors, and where surgery would be difficult or invasive.[105]

The treatment may result in peeling, crusting, or blistering, and hyperpigmentation may occur on darkly pigmented skin.

1st line – topical chemotherapy

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ACUTE
|
SCC in situ (Bowen disease)
1st line – 

topical chemotherapy

Topical chemotherapy with fluorouracil-based regimens (e.g,. fluorouracil with or without calcipotriene) are preferred.[73]

Fluorouracil targets abnormal cells by providing high local concentrations of this chemotherapeutic agent without adverse systemic effects, and it has been demonstrated to have a significant clearance rate for SCC.[97][98]​ The advantage of this approach is that numerous lesions in an affected area are treated. In addition, treatment can be performed at home.

Responsive lesions will become erosive within a few days to weeks depending on the concentration of medication and frequency of application. After a crusted stage, the erosions re-epithelialize to leave cytologically normal skin.

Strict sun avoidance is highly recommended.

Primary options

fluorouracil topical: (5%) apply to the affected area(s) twice daily for 3-6 weeks

OR

fluorouracil topical: (5%) apply to the affected area(s) twice daily for 3-6 weeks

and

calcipotriene topical: (0.005%) apply to the affected area(s) once or twice daily for 3-6 weeks

2nd line – conventional surgical excision or Mohs surgery

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ACUTE
|
SCC in situ (Bowen disease)
2nd line – 

conventional surgical excision or Mohs surgery

Patients with squamous cell carcinoma (SCC) in situ should be followed closely, and tumors that do not respond or recur should be excised.

Conventional surgery is used for noncosmetically sensitive locations. Mohs micrographic surgery may be used for tumors on cosmetically sensitive areas (e.g., face), tumors >2 cm in diameter, and all recurrent tumors.

UK guidelines recommend excision with a clinical peripheral surgical margin of ≥4 mm, ≥6 mm, or ≥10 mm for low-risk, high-risk, or very-high-risk cutaneous SCC tumor, respectively.[92] In the US, standard excision with a 4- to 6-mm clinical margin is recommended for local low-risk cutaneous SCC; wider surgical margin, with intraoperative margin control, and postoperative margin assessment, is required for high-risk tumors.[73][83]​ Tumor diameter, thickness, perineural invasion, and patient factors determine degree of tumor risk.[73][92]

In the UK, ≥1 mm histologic clearance of SCC excision from all margins is recommended.[92] This is achieved by excising sufficient peripheral and deep tissues. For mobile lesions, the deep margin should be within the next clear surgical plane. For deeply infiltrating lesions at any site, achieving a clear/uninvolved deep margin may require excision of fascia, muscle, bone, or underlying structures. Where possible, uninvolved margins should be confirmed histologically.[92]

In the US, biopsy at presentation is also recommended with subsequent excision with 4-6 mm clinical margin recommended in first instance for low-risk tumors. US guidance recommends high-risk tumors are assessed on a case-by-case basis.[73]

Mohs surgery provides the highest cure rate for SCC, at >97% for primary tumors. In addition, it allows for optimal tissue sparing, as only the additional areas that carry tumors are removed.[108][109] Local recurrence rates following Mohs has been reported at 16%, with rates of nodal metastasis at 3% for patients with verrucous carcinoma.[110] 

In 2012, the American Academy of Dermatology, the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery published appropriate use criteria for Mohs micrographic surgery, which detail specific indications for performing Mohs surgery.[111]

Consider – radiation therapy

Back
ACUTE
|
SCC in situ (Bowen disease)
Consider – 

radiation therapy

Treatment recommended for SOME patients in selected patient group

Referral to a radiation oncologist for adjuvant radiation therapy may be indicated for aggressive tumor subtypes.[127][128]

Adjuvant radiation therapy may be indicated for patients with positive or negative margins.[73]

2nd line – radiation therapy

Back
ACUTE
|
SCC in situ (Bowen disease)
2nd line – 

radiation therapy

Radiation therapy is an option for treatment of Bowen disease, particularly those cases that are deemed unresectable or in patients who are poor surgical candidates. A high rate of tumor control, with minimal morbidity and preservation of normal tissues, has been demonstrated.[106]

invasive SCC

1st line – conventional surgical excision or electrodessication and curettage or shave excision

Back
ACUTE
|
invasive SCC
|
noncosmetically sensitive locations, <2 cm in diameter
1st line – 

conventional surgical excision or electrodessication and curettage or shave excision

In the first instance, standard surgical excision should be offered to people with a resectable squamous cell carcinoma (SCC).[73] The 5-year cure rate with standard excision for primary SCC is 92%, for recurrent SCC the cure rate is 77%.[107] When performing surgery, peripheral tumor margins should be determined under a bright light with magnification or dermoscopy.

UK guidelines recommend excision with a clinical peripheral surgical margin of ≥4 mm, ≥6 mm, or ≥10 mm for low-risk, high-risk, or very-high-risk cutaneous SCC tumor, respectively.[92] In the US, standard excision with a 4- to 6-mm clinical margin is recommended for local low-risk cutaneous SCC; wider surgical margin, with intraoperative margin control, and postoperative margin assessment, is required for high-risk tumors.[73][83]​ Tumor diameter, thickness, perineural invasion, and patient factors determine degree of tumor risk.[73][92]

In the UK, ≥1 mm histologic clearance of SCC excision from all margins is recommended.[92] This is achieved by excising sufficient peripheral and deep tissues. For mobile lesions, the deep margin should be within the next clear surgical plane. For deeply infiltrating lesions at any site, achieving a clear/uninvolved deep margin may require excision of fascia, muscle, bone, or underlying structures. Where possible, uninvolved margins should be confirmed histologically.[92]

In the US, biopsy at presentation is also recommended with subsequent excision with 4-6 mm clinical margin recommended in first instance for low-risk tumors. US guidance recommends high-risk tumors are assessed on a case-by-case basis.[73]

Shave removal is an option for some low-risk SCCs. It is most suitable for dermal and epidermal lesions.[73] The tumor is removed by making a transverse cut with a scalpel underneath the lesion.[112] 

Electrodessication and curettage is another option for treatment of some low-risk SCCs, but it may cause dyspigmentation and scarring.[101] The dermatologist curettes the clinically apparent tumor with a sharp round instrument, then coagulates the wound bed with electric current to dryness. The eschar is curetted twice more with subsequent electrodessication. 

Consider – radiation therapy

Back
ACUTE
|
invasive SCC
|
noncosmetically sensitive locations, <2 cm in diameter
Consider – 

radiation therapy

Treatment recommended for SOME patients in selected patient group

Referral to a radiation oncologist for adjuvant radiation therapy may be indicated for aggressive tumor subtypes.[127][128]

Adjuvant radiation therapy may be indicated for patients with positive or negative margins.[73]

1st line – Mohs surgery

Back
ACUTE
|
invasive SCC
|
cosmetically sensitive locations, >2 cm in diameter
1st line – 

Mohs surgery

Mohs micrographic surgery is used for tumors on cosmetically sensitive areas (e.g., face), tumors >2 cm in diameter, and all recurrent tumors.

Mohs surgery provides the highest cure rate for squamous cell carcinoma, at >97% for primary tumors. In addition, it allows for optimal tissue sparing, as only the additional areas that carry tumors are removed.[108][109] Local recurrence rates following Mohs have been reported at 16%, with rates of nodal metastasis at 3% for patients with verrucous carcinoma.[110] 

In 2012, the American Academy of Dermatology, the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery published appropriate use criteria for Mohs micrographic surgery, which detail specific indications for performing Mohs surgery.[111]

Consider – radiation therapy

Back
ACUTE
|
invasive SCC
|
cosmetically sensitive locations, >2 cm in diameter
Consider – 

radiation therapy

Treatment recommended for SOME patients in selected patient group

Referral to a radiation oncologist for adjuvant radiation therapy may be indicated for aggressive tumor subtypes.[127][128]

Adjuvant radiation therapy may be indicated for patients with positive or negative margins.[73]

2nd line – radiation therapy

Back
ACUTE
|
invasive SCC
|
cosmetically sensitive locations, >2 cm in diameter
2nd line – 

radiation therapy

For nonsurgical candidates, definitive radiation therapy may be considered after discussion with a multidisciplinary team.[73]

metastatic SCC

1st line – conventional surgical excision

Back
ACUTE
|
metastatic SCC
|
noncosmetically sensitive locations, <2 cm in diameter
1st line – 

conventional surgical excision

Treatment includes surgery (excision of the tumor and involved lymph nodes), radiation therapy, and often chemotherapy.[113][114]

Conventional surgery is used for noncosmetically sensitive locations.

UK guidelines recommend excision with a clinical peripheral surgical margin of ≥4 mm, ≥6 mm, or ≥10 mm, for low-risk, high-risk, or very-high-risk cutaneous squamous cell carcinoma (SCC) tumor, respectively.[92] In the US, standard excision with a 4- to 6-mm clinical margin is recommended for local low-risk cutaneous SCC; wider surgical margin, with intraoperative margin control, and postoperative margin assessment, is required for high-risk tumors.[73][83]​​​​ Tumor diameter, thickness, perineural invasion, and patient factors determine degree of tumor risk.[73][92]​​​ 

Reconstruction by facial plastic surgery may also be required.

For solid organ transplant recipients who are at high risk for squamous cell carcinoma, Mohs micrographic surgery is usually recommended rather than standard excision.

Consider – neoadjuvant cemiplimab

Back
ACUTE
|
metastatic SCC
|
noncosmetically sensitive locations, <2 cm in diameter
Consider – 

neoadjuvant cemiplimab

Treatment recommended for SOME patients in selected patient group

Neoadjuvant treatment with cemiplimab, a human monoclonal antibody targeting programmed death receptor-1 (PD-1) on T cells, may be considered for patients with squamous cell carcinoma (SCC), after multidisciplinary discussion, if the tumor has very rapid growth, in-transit metastasis, lymphovascular invasion, is borderline resectable, or surgery alone may not be curative or may result in significant functional limitation.[73] 

Early phase trials have demonstrated promising results for patients with SCC treated with neoadjuvant cemiplimab.[115][116][117]

See local specialist protocol for dosing guidelines.

Primary options

cemiplimab

Consider – radiation therapy

Back
ACUTE
|
metastatic SCC
|
noncosmetically sensitive locations, <2 cm in diameter
Consider – 

radiation therapy

Treatment recommended for SOME patients in selected patient group

Radiation therapy can be used as an adjunct to the surgical treatment of metastatic squamous cell carcinoma (SCC) and has been shown to improve outcomesin patients with positive or negative postoperative margins.[73][113]​​[124]​​​​​ There is some evidence to suggest that improved outcomes may be seen in patients with high-risk SCC with concurrent or sequential immune checkpoint inhibition and postoperative radiation therapy.[125]

2nd line – cemiplimab or pembrolizumab

Back
ACUTE
|
metastatic SCC
|
noncosmetically sensitive locations, <2 cm in diameter
2nd line – 

cemiplimab or pembrolizumab

Treatment with cemiplimab or pembrolizumab, anti-PD-1 monoclonal antibodies, can be used in patients with locally recurrent or metastatic disease not amenable to surgery or radiation therapy.[73] In Europe and the UK, only cemiplimab is approved for this indication.[118]​​[119]

One retrospective, observational, multicenter study reported that real-world data confirmed the efficacy and safety of cemiplimab for patients with advanced SCC, but that efficacy may differ slightly between European and US regions, which may be associated with different genetic backgrounds.[120]​​ 

See local specialist protocol for dosing guidelines.

Primary options

cemiplimab

OR

pembrolizumab

3rd line – systemic therapy

Back
ACUTE
|
metastatic SCC
|
noncosmetically sensitive locations, <2 cm in diameter
3rd line – 

systemic therapy

For patients with unresectable squamous cell carcinoma (SCC), systemic therapy (plus concurrent radiation therapy) with cisplatin, carboplatin with or without paclitaxel, or an EGFR inhibitor monoclonal antibody such as cetuximab can be considered in select cases.[73] A clinical trial should be considered for these patients.[73]

For nonsurgical candidates, for whom curable radiation therapy is not feasible, who are not suited to, or have progressed with immune checkpoint inhibitors and clinical trials, systemic therapy alone with carboplatin plus paclitaxel (with or without cetuximab), or an EGFR inhibitor alone (e.g., cetuximab) may be considered.[73]

Studies have shown efficacy of EGFR inhibitors in decreasing SCCs that are not amenable to surgery, especially of the head and neck.[121][122]​​ Some evidence suggests that EGFR inhibitors may be considered for patients with advanced cSCC who have contraindications, or who progress on, anti-PD-1 monoclonal antibodies.[123] 

See local specialist protocol for dosing guidelines.

Primary options

cisplatin

OR

carboplatin

OR

carboplatin

and

paclitaxel

OR

cetuximab

OR

carboplatin

and

paclitaxel

and

cetuximab

Consider – radiation therapy

Back
ACUTE
|
metastatic SCC
|
noncosmetically sensitive locations, <2 cm in diameter
Consider – 

radiation therapy

Treatment recommended for SOME patients in selected patient group

Radiation therapy can be used in conjunction with systemic therapy with cisplatin, carboplatin with or without paclitaxel, or an EGFR inhibitor monoclonal antibody (e.g., cetuximab).[73]

1st line – Mohs surgery

Back
ACUTE
|
metastatic SCC
|
cosmetically sensitive locations, >2 cm in diameter
1st line – 

Mohs surgery

Mohs micrographic surgery is used for tumors on cosmetically sensitive areas (e.g., face), tumors >2 cm in diameter, and all recurrent tumors.

UK guidelines recommend excision with a clinical peripheral surgical margin of ≥4 mm, ≥6 mm, or ≥10 mm, for low-risk, high-risk, or very-high-risk cutaneous squamous cell carcinoma (SCC) tumor, respectively.[92] In the US, standard excision with a 4- to 6-mm clinical margin is recommended for local low-risk cutaneous SCC; wider surgical margin, with intraoperative margin control, and postoperative margin assessment, is required for high-risk tumors.[73][83]​​​​ Tumor diameter, thickness, perineural invasion, and patient factors determine degree of tumor risk.[73][92]

Reconstruction by facial plastic surgery may also be required.

In 2012, the American Academy of Dermatology, the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery published appropriate use criteria for Mohs micrographic surgery, which detail specific indications for performing Mohs surgery.[111]

Consider – neoadjuvant cemiplimab

Back
ACUTE
|
metastatic SCC
|
cosmetically sensitive locations, >2 cm in diameter
Consider – 

neoadjuvant cemiplimab

Treatment recommended for SOME patients in selected patient group

​Neoadjuvant treatment with cemiplimab, a human monoclonal antibody targeting programmed death receptor-1 (PD-1) on T cells, may be considered for patients with squamous cell carcinoma (SCC), after multidisciplinary discussion, if the tumor has very rapid growth, in-transit metastasis, lymphovascular invasion, is borderline resectable, or surgery alone may not be curative or may result in significant functional limitation.[73]

Early phase trials have demonstrated promising results for patients with SCC treated with neoadjuvant cemiplimab.[115][116][117]

See local specialist protocol for dosing guidelines.

Primary options

cemiplimab

Consider – radiation therapy

Back
ACUTE
|
metastatic SCC
|
cosmetically sensitive locations, >2 cm in diameter
Consider – 

radiation therapy

Treatment recommended for SOME patients in selected patient group

Radiation therapy can be used as an adjunct to the surgical treatment of metastatic squamous cell carcinoma (SCC) and has been shown to improve outcomesin patients with positive or negative postoperative margins.[73][113]​​[124]​​​​ There is some evidence to suggest that improved outcomes may be seen in patients with high-risk SCC with concurrent or sequential immune checkpoint inhibition and postoperative radiation therapy.[125]

2nd line – cemiplimab or pembrolizumab

Back
ACUTE
|
metastatic SCC
|
cosmetically sensitive locations, >2 cm in diameter
2nd line – 

cemiplimab or pembrolizumab

Treatment with cemiplimab or pembrolizumab, anti-PD-1 monoclonal antibodies, can be used in patients with locally recurrent or metastatic disease not amenable to surgery or radiation therapy.[73] In Europe and the UK, only cemiplimab is approved for this indication.[118][119]

One retrospective, observational, multicenter study reported that real-world data confirmed the efficacy and safety of cemiplimab for patients with advanced SCC, but that efficacy may differ slightly between European and US regions, which may be associated with different genetic backgrounds.[120]​​​ 

See local specialist protocol for dosing guidelines.

Primary options

cemiplimab

OR

pembrolizumab

3rd line – systemic therapy

Back
ACUTE
|
metastatic SCC
|
cosmetically sensitive locations, >2 cm in diameter
3rd line – 

systemic therapy

​For patients with unresectable squamous cell carcinoma (SCC), systemic therapy (plus concurrent radiation therapy) with cisplatin, carboplatin with or without paclitaxel, or an EGFR inhibitor monoclonal antibody such as cetuximab can be considered in select cases.[73]​ A clinical trial should be considered for these patients.[73]

​For nonsurgical candidates, for whom curable radiation therapy is not feasible, who are not suited to, or have progressed with immune checkpoint inhibitors and clinical trials, systemic therapy alone with carboplatin plus paclitaxel (with or without cetuximab), or an EGFR inhibitor alone (e.g., cetuximab) may be considered.[73]

​Studies have shown efficacy of EGFR inhibitors in decreasing SCCs that are not amenable to surgery, especially of the head and neck.[121][122]​ Some evidence suggests that EGFR inhibitors may be considered for patients with advanced cSCC who have contraindications to, or who progress on, anti-PD-1 monoclonal antibodies.[123]

See local specialist protocol for choice of appropriate chemotherapy regimens and dosing guidelines.

Primary options

cisplatin

OR

carboplatin

OR

carboplatin

and

paclitaxel

OR

cetuximab

OR

carboplatin

and

paclitaxel

and

cetuximab

Consider – radiation therapy

Back
ACUTE
|
metastatic SCC
|
cosmetically sensitive locations, >2 cm in diameter
Consider – 

radiation therapy

Treatment recommended for SOME patients in selected patient group

​Radiation therapy can be used in conjunction with systemic therapy with cisplatin, carboplatin with or without paclitaxel, or an EGFR inhibitor monoclonal antibody such as cetuximab.[73]

ONGOING

immunocompromised or high risk of metastatic disease

1st line – oral retinoid

Back
ONGOING
|
immunocompromised or high risk of metastatic disease
1st line – 

oral retinoid

Oral retinoids have been shown to prevent recurrence and progression, particularly in immunosuppressed patients (e.g., AIDS, solid organ transplant recipients), and also in patients with early-onset high-risk (i.e., large and invasive) tumors, high sun exposure, and lightly pigmented skin.[41][126]

Primary options

acitretin: 25-50 mg orally once daily for 9-12 months

OR

isotretinoin: 0.5 to 1 mg/kg/day orally for 9-12 months

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Choose a patient group to see our recommendations

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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