GuidelinesEuropean interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 2. Treatment
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.
References (133)
- et al.
Advanced cutaneous squamous cell carcinoma: a retrospective analysis of patient profiles and treatment patterns-Results of a non-interventional study of the DeCOG
Eur J Cancer
(2018) - et al.
Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study
Lancet Oncol
(2008) - et al.
Tumor recurrence 5 years after treatment of cutaneous basal cell carcinoma and squamous cell carcinoma
J Invest Dermatol
(2013) - et al.
Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years
J Am Acad Dermatol
(2005) - et al.
Clinical outcomes in high-risk squamous cell carcinoma patients treated with Mohs micrographic surgery alone
J Am Acad Dermatol
(2019) - et al.
Surgical margins for excision of primary cutaneous squamous cell carcinoma
J Am Acad Dermatol
(1992) - et al.
British Association of D, British Association of Plastic S. Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma
Br J Plast Surg
(2003) - et al.
Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline
Eur J Cancer
(2015) - et al.
Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection
J Am Acad Dermatol
(1992) - et al.
Management of regional metastatic disease in head and neck cutaneous malignancy. 1. Cutaneous squamous cell carcinoma
Br J Oral Maxillofac Surg
(2014)
Treatment results of regional metastasis from cutaneous head and neck squamous cell carcinoma
Eur J Surg Oncol
Efficacy of curettage alone for invasive cutaneous squamous cell carcinoma: a retrospective cohort study
J Am Acad Dermatol
Successful treatment of keratoacanthoma with intralesional fluorouracil
J Am Acad Dermatol
Intralesional methotrexate treatment for keratoacanthoma tumors: a retrospective study and review of the literature
J Am Acad Dermatol
Radiotherapy for skin cancers of the face, head, and neck
Facial Plast Surg Clin North Am
Adjuvant radiotherapy after excision of cutaneous squamous cell carcinoma
J Am Acad Dermatol
Phase 1 study of erlotinib plus radiation therapy in patients with advanced cutaneous squamous cell carcinoma
Int J Radiat Oncol Biol Phys
Combination of post-operative radiotherapy and cetuximab for high-risk cutaneous squamous cell cancer of the head and neck: a propensity score analysis
Oral Oncol
A prospective clinical trial to assess lapatinib effects on cutaneous squamous cell carcinoma and actinic keratosis
ESMO Open
Tumor-associated macrophages in the cutaneous SCC microenvironment are heterogeneously activated
J Invest Dermatol
Somatic mutation of epidermal growth factor receptor in a small subset of cutaneous squamous cell carcinoma
J Invest Dermatol
Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma
Ann Oncol
Efficacy of cetuximab for unresectable or advanced cutaneous squamous cell carcinoma–a report of eight cases
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
Cutaneous squamous cell carcinoma: review of the eighth edition of the American Joint Committee on Cancer Staging Guidelines, Prognostic Factors, and Histopathologic Variants
Adv Anat Pathol
Excision margins for nonmelanotic skin cancer
Plast Reconstr Surg
Squamocellular carcinoma of the skin: clinicopathological features predicting the involvement of the surgical margins and review of the literature
Dermatology
Guidelines for the diagnosis and treatment of cutaneous squamous cell carcinoma and precursor lesions
J Eur Acad Dermatol Venereol
Non-melanoma Skin Cancer in Canada Chapter 5: management of Squamous Cell Carcinoma
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
Non-melanoma skin cancer: United Kingdom National Multidisciplinary Guidelines
J Laryngol Otol
Surgery and adjuvant radiotherapy in patients with cutaneous head and neck squamous cell carcinoma metastatic to lymph nodes: combined treatment should be considered best practice
Laryngoscope
Management of the neck in metastatic cutaneous squamous cell carcinoma of the head and neck
Curr Opin Otolaryngol Head Neck Surg
Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous carcinoma of the parotid gland
Head Neck
Patterns of lymph node spread of cutaneous squamous cell carcinoma of the head and neck
Head Neck
Outcome of patients treated surgically for lymph node metastases from cutaneous squamous cell carcinoma of the head and neck
Head Neck
Predicting the pattern of regional metastases from cutaneous squamous cell carcinoma of the head and neck based on location of the primary
Head Neck
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