European interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 2. Treatment

doi:10.1016/j.ejca.2020.01.008

European Journal of Cancer

Volume 128, March 2020, Pages 83-102

https://doi.org/10.1016/j.ejca.2020.01.008 Get rights and content

Highlights

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Surgical excision with negative margins is an important goal whenever feasible.
•
Radiotherapy is indicated for inoperable cSCC or patients not suitable for surgical intervention.
•
Multidisciplinary board decisions are necessary in the management of patients with advanced disease.
•
Anti-PD-1 antibody therapy is first-line systemic treatment for locally advanced or mcSCC.
•
Follow-up evaluations depend on underlying risk characteristics.

Abstract

In order to update recommendations on treatment, supportive care, education and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization of Research and Treatment of Cancer was formed. Recommendations were based on evidence-based literature review, guidelines and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable) and distant metastatic cSCC. For common primary cSCC (the most frequent cSCC type), first-line treatment is surgical excision with postoperative margin assessment or microscopically controlled sugery. Safety margins containing clinical normal-appearing tissue around the tumour during surgical excision and negative margins as reported in the pathology report are necessary to minimise the risk of local recurrence and metastasis. In case of positive margins, a re-excision shall be done, for operable cases. Lymph node dissection is recommended for cSCC with cytologically or histologically confirmed regional nodal involvement. Radiotherapy should be considered as curative treatment for inoperable cSCC, or for non-surgical candidates. Anti-PD-1 antibodies are the first-line systemic treatment for patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiation, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drug Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiation therapy. Multidisciplinary board decisions are mandatory for all patients with advanced disease who require more than surgery. Patients should be engaged with informed decisions on management and be provided with best supportive care to optimise symptom management and improve quality of life. Frequency of follow-up visits and investigations for subsequent new cSCC depend on underlying risk characteristics.

Section snippets

Information about the guideline

The European Interdisciplinary Guidelines on invasive squamous cell carcinoma of the skin were written as a uniform text and then published in 2 separate but integral parts: Part 1 on definitions, epidemiology, etiopathogenesis, diagnosis, risk classification, staging and prevention and Part 2 on treatments, supportive care, patient education and follow-up. Information about the Guidelines is detailed in Stratigos et al. Part 1, including the information about societies in charge, financing of

General considerations for the treatment of cSCC

Clearance of the tumour is the main goal of surgery which is the primary treatment of cSCC. Additionally, preservation of function and cosmesis are relevant objectives of treatment. Most cSCC are successfully treated with surgical excision alone with a good prognosis and cure rates greater than 90% [2].

Radiotherapy (RT) may be considered as a primary treatment in patients who are not candidates for surgery (e.g. locally advanced disease, comorbidities or declined surgery) or in cases when

Surgery for common primary cSCC

Surgical excision is considered the first-line treatment of primary cSCC, regardless of the age-group and anatomic location. Surgery provides a high rate of clinical and microscopic complete resection (R0 surgery).

Two different surgical procedures may be offered in patients with primary cSCC: conventional surgery with safety margins and micrographically controlled surgery (MCS). MCS provides the highest rate of R0 resection, above 90%, and lower recurrence rates (0%–4%) compared to conventional

Surgery for regional nodal disease

The evidence about the management of regional nodal disease in patients with cSCC is limited and largely based on studies performed in head and neck mucosal SCC [31]. It is likely that patients with nodal metastases from cSCC should be managed surgically similarly to patients with other skin cancers (melanoma or Merkel cell carcinoma). For all tumours not amenable to surgery (due to patient-related factors or when the intention of a R0-resectability cannot be achieved), non-operative therapies

Curettage and electrodessication

There are no prospective studies comparing curettage and electrodessication (C&E) with other treatments. A systemic review and pooled analysis of observational studies reported low recurrence rates for small cSCC (<2 cm) [11]. Expert consensus in the AAD guidelines state that C&E may be considered for small, low-risk primary cSCC (based on National Comprehensive Cancer Network risk stratification) [16,26]. Curettage and cautery (2 cycles) in experienced hands can be performed in small, low-risk

Primary definitive RT

Definitive primary RT represents a good alternative and curative treatment strategy to surgery for small cSCCs. RT may be considered as a primary treatment in patients who are not candidates for surgery (e.g. lacSCC, presence of comorbidities or decline of surgery) or in cases when curative surgery is not possible or could be disfiguring or burdened by poor functional outcome, especially cSCCs located on the face (i.e. eyelid, nose and lip) or large lesions on the ear, forehead or scalp.

Adjuvant systemic therapy

There are no solid data to support the use of adjuvant systemic treatment in localised cSCC after RO resection [62,[65], [66], [67], [68], [69]]. There was no improvement in time to recurrence or time to second primary tumours with adjuvant 13-cis-retinoic acid plus interferon alpha [67]. Adjuvant chemotherapy (oral capecitabine and other systemic cytotoxic drugs) or targeted therapies (EGFR inhibitors) should not be recommended, because robust evidence about efficacy based on survival data is

Neoadjuvant therapy

Neoadjuvant therapy aims to reduce the size of a tumour before surgery, so that there is a smaller surgical defect and easier reconstruction. There is a limited number of small studies on neoadjuvant EGFR inhibitor therapy [[70], [71], [72], [73]]. A recommendation cannot be given on the use of neoadjuvant therapy due to lack of adequate evidence. Publication of results for neoadjuvant cemiplimab are awaited.

Treatment for in-transit metastases

Satellite or in-transit metastases should be removed surgically if the number, size and location allow complete removal of the metastatic sites. According to a case series, adjuvant radiation therapy can be helpful in such cases [74]. For multiple unresectable metastases on the limbs, amputation used to be a common option; however, currently it is no longer performed as it has no proven impact on the prognosis and several local and systemic alternatives are available to prevent mutilation [74].

Immunotherapy: immune checkpoint inhibitors

Until recently, no systemic therapy was formally approved for the treatment of mcSCC. Similar to other ultraviolet radiation–driven skin cancers, cSCC is among the cancers with the highest rate of somatic mutations [79] and mutated proteins can serve as neoantigens that can be recognised by the immune system [80]. Increased PD-1 and PD-ligand 1 (PD-L1) expression with immunohistochemistry has been reported in cSCC compared to normal skin, but with no correlation to clinical response [81]. Also,

Clinical trials

Patient participation in clinical trials is encouraged. Pembrolizumab is being evaluated in clinical trials for lacSCC or mcSCC, either alone (NCT02964559, NCT03284424) or in combination with abexinostat, a broad-spectrum phenyl hydroxamic acid inhibitor of histone deacetylase (NCT03590054), or cetuximab (NCT03082534), or Oncolytic MG1 Expressing MAGE-A3 (MG1-MAGEA3) with Adenovirus Vaccine Expressing MAGE-A3 (NCT03773744). Also, cemiplimab is being evaluated for recurrent stage II-IV head and

Best supportive care

When no further curative therapy is possible, palliative therapy (surgery, RT, electrochemotherapy) aims to control tumour extension and relieve symptoms [111,116]. RT is particularly helpful as a palliative treatment, in order to relieve pain, to stop haemorrhage and to limit tumour extension to adjacent critical areas such as the orbits or oral cavity [119]. In these cases, a combined treatment of RT with chemotherapy or with cetuximab or other EGFR inhibitors may be used. A number of

Follow-up

Patients with cSCC should be closely followed up for the early detection of recurrences and for the development of new keratinocyte cancer and melanoma. The relative risk for development of melanoma after diagnosis of a keratinocyte cancer was reported to be 1.99 for men and 2.58 for women based on 2 large cohort studies [128]. In a cohort of 1426 cSCC patients in the United States, 5- and 10-year risks of further cSCC were estimated to be 42.1% and 69.1%, respectively [129], and the

Patient education

When diagnosing common primary cSCC, the clinician will need to give information about the type of cSCC diagnosed and the risk of relapse or metastasis. Patients should be reminded that most cSCCs are well-differentiated tumours which have a low risk of recurrence and/or metastasis. Patients may need support from clinical nurse specialists in case of disfiguring surgery or the delivery of bad news and need to be offered access to support services when deemed necessary. Self-examination should

Funding sources

The development of the current set of guideline was supported solely by funds of the EADO which were used to mainly support the consensus meeting.

Conflict of interest statement

Dr. Stratigos reports personal fees and/or research support from Novartis, Roche, BMS, AbbVie, Sanofi, Regeneron, Genesis Pharma, outside the submitted work. Dr. Garbe reports personal fees from Amgen, personal fees from MSD, grants and personal fees from Novartis, grants and personal fees from NeraCare, grants and personal fees from BMS, personal fees from Pierre Fabre, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, outside the submitted

Acknowledgements

Jørgen Johansen, MD, Associate Professor, Dept of Oncology, Odense University Hospital for assistance with section on radiotherapy.

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GuidelinesEuropean interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 2. Treatment

Highlights

Abstract

Section snippets

Information about the guideline

General considerations for the treatment of cSCC

Surgery for common primary cSCC

Surgery for regional nodal disease

Curettage and electrodessication

Primary definitive RT

Adjuvant systemic therapy

Neoadjuvant therapy

Treatment for in-transit metastases

Immunotherapy: immune checkpoint inhibitors

Clinical trials

Best supportive care

Follow-up

Patient education

Funding sources

Conflict of interest statement

Acknowledgements

Eur J Cancer

Lancet Oncol

J Invest Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

Br J Plast Surg

Eur J Cancer

J Am Acad Dermatol

Br J Oral Maxillofac Surg

Eur J Surg Oncol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

Facial Plast Surg Clin North Am

J Am Acad Dermatol

Int J Radiat Oncol Biol Phys

Oral Oncol

ESMO Open

J Invest Dermatol

J Invest Dermatol

Ann Oncol

Clin Oncol (R Coll Radiol)

The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors

J Surg Oncol

Cetuximab-radiotherapy combination in the management of locally advanced cutaneous squamous cell carcinoma

J Med Imaging Radiat Oncol

Mohs surgery is effective for high-risk cutaneous squamous cell carcinoma

Dermatol Surg

Recurrence rates of cutaneous squamous cell carcinoma of the head and neck after Mohs micrographic surgery vs. standard excision: a retrospective cohort study

Br J Dermatol

Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies

BMJ

A confusing world: what to call histology of three-dimensional tumour margins?

J Eur Acad Dermatol Venereol

S1 guideline: microscopically controlled surgery (MCS)

J Dtsch Dermatol Ges

Surgical monotherapy versus surgery plus adjuvant radiotherapy in high-risk cutaneous squamous cell carcinoma: a systematic review of outcomes

Dermatol Surg

NCCN Clinical Practice Guidelines in Oncology. Squamous cell Skin Cancer

Effective excision of cutaneous squamous cell carcinoma of the face using analysis of intra-operative frozen sections from the whole specimen

J Surg Oncol

False-negative rate of intraoperative frozen section margin analysis for complex head and neck nonmelanoma skin cancer excisions

Clin Exp Dermatol

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Adv Anat Pathol

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J Cutan Med Surg

Guidelines of care for the management of cutaneous squamous cell carcinoma

J Am Acad Dermatol

Clinical Practice Guidelines in Oncology. Cutaneous Melanoma

Brief S2k guidelines – cutaneous squamous cell carcinoma

J Dtsch Dermatol Ges

Guidelines
European interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 2. Treatment