Actinic Keratosis and Cutaneous Squamous Cell Carcinoma
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Background: Cutaneous squamous cell carcinoma (cSCC) and its precursors, actinic keratoses (AK), are common. Physicians of multiple specialties are confronted with their treatment.
Methods: This review is based on publications retrieved by a selective search in PubMed, as well as on the German guidelines on AK and cSCC, skin cancer prevention, and surgery with histologic guidance.
Results: Local treatments for AK include lesional cryotherapy, curettage, and laser ablation as well as field-directed treatments with topical agents, e.g., diclofenac plus hyaluronic acid, imiquimod, 5-fluorouracil, ingenol mebutate, and photodynamic therapy. These treatments can be administered in various sequences or combinations, depending on individual factors and the stage of the disease. The gold standard of treatment for cSCC is histologically confirmed complete resection; radiotherapy is an alternative. Locally uncontrollable or metastatic disease is treated with systemic drugs. The use of various chemotherapeutic agents, EGFR-directed therapies, and the PD-I inhibitor cemiplimab, either singly or in combination, has been described in uncontrolled trials and case series. Cemiplimab has a reported response rate of 47% and was recently approved for the treatment of advanced cSCC.
Conclusion: There are many options for the treatment of AK and cSCC that must be considered in the interdisciplinary care of these entities.
Actinic keratosis (AK) consists of the intradermal proliferation of histologically atypical keratinocytes in an area of skin that has been chronically damaged by exposure to ultraviolet light (UV). AK presents as reddish or brownish spots or plaques with increased keratosis on areas of the skin that have been exposed to the sun. If the entire thickness of the skin contains atypical keratinocytes, but the basal membrane is preserved, this is called carcinoma in situ, or Bowen’s disease (1). Multiple lesions in a contiguous area of skin with visible UV-induced skin damage (e.g., on the scalp, forehead, or dorsa of the hand) are called field cancerization (Figure 1a) (1). In cutaneous squamous cell carcinoma (cSCC), the atypical keratinocytes break through the basal membrane; this can manifest itself with nodular growth (Figure 1b) (1). cSCC can arise de novo or on the basis of preexisting AK. The probability and speed of the transition from AK to cSCC is individual, highly variable, and unpredictable. In a systematic review, the progression rate of a single AK to cSCC was variably estimated at 0% to 0.075% per lesion per year. A higher progression rate of 0.53% per lesion per year was estimated if the patient already had cSCC elsewhere. At the same time, however, single AK were found to have high regression rates ranging from 15% to 53% per year, as well as long-term recurrence rates above 50% (2). In the review article, this dynamic was attributed in part to methodological weaknesses in the published studies (e.g., missing data on treatments received and on sun-screening methods, as well as high dropout rates). Yet the literature and clinical experience do, in fact, show that AK and light-induced skin damage are a dynamic rather than static pathological process (2).
The age-standardized incidence rate of cSCC in Germany in the period 2010 to 2014 was 26.90 per 100 000 persons per year, which was 30% higher than the corresponding figure for 2005 to 2009 (1). After a diagnosis of cSCC, 50% of patients go on to develop further epithelial skin tumors, most often within 1 year of the initial diagnosis (1).
Cumulative UV exposure is the main risk factor for AK and cSCC (Box 1). If a patient has six or more AK, a cSCC, or field cancerization over an area of at least 4 cm2 on a region of skin that is exposed to UV light because of the patient’s work, the possible presence of an occupational disease should be assessed (no. 5103 in the German classification of occupational diseases). Immune compromise, e.g., in transplant recipients and patients with hematologic cancers such as chronic lymphocytic leukemia, is also associated with a higher incidence and a more aggressive course of cSCC (3).
The risk of recurrence and metastasis of cSCC is low with appropriate therapy. Clinical and histological risk factors have been determined (Box 2). In a series of 114 patients with metastatic cSCC, 46 (40%) had locoregional metastasis in the skin and lymph nodes (Figure 1c), 35 (31%) had distant metastases (usually to the lungs and pleura), and 33 (29%) had simultaneous locoregional and distant metastases (e63). Curative treatment is considered no longer possible in patients with distant metastases or a regional metastasis or local recurrence that cannot be completely controlled with surgery or radiotherapy (e63).
This article is intended to enable the reader to:
- Gain an up-to-date understanding of the clinical features and prognosis of actinic keratosis and cutaneous squamous cell carcinoma
- Become familiar with the essential procedures for treatment of these lesions
- Assess the advantages and limitations of the various treatment options
This review is based on pertinent publications retrieved by a systematic review of the Medline database, as well as on the German guidelines on AK and cSCC, skin cancer prevention, and histologically guided surgery. The evidence levels are taken from the assessments contained in the German clinical practice guidelines on AK and cSCC, which employ the system of the Oxford Center for Evidence-Based Medicine in its version of 2011 (1). Evidence levels are given on a scale from 1 to 5, with 1 being the highest and 5 the lowest.
It cannot yet be reliably determined on clinical and histological grounds which AK lesions will undergo transformation into invasive cSCC and which will not. Important indicators of the individual risk of developing cSCC include immune suppression, a prior history of epithelial skin cancer, high cumulative UV exposure, and the number of lesions present. In view of this and the fact that AK is perceived as a chronic, progressive disease, adequate treatment for all cases of AK is recommended after critical evaluation of the patient’s life expectancy, comorbidities, and individual preferences.
There are many treatments for AK (Table 1, Figure 2). Lesion-directed treatments include procedures with the scalpel (e.g., shave excision), liquid nitrogen (cryosurgery), or laser (e.g., erbium/YAG; CO2). These are provided directly by the physician to the patient and are appropriate for isolated, well-demarcated lesions. An advantage of the surgical approach is that it provides for histopathological control of the clinical diagnosis and the complete removal of the lesion; its disadvantages include the need for local anesthesia, bleeding, and possible scar formation. Cryosurgery and laser therapy can be performed very rapidly in experienced hands but can cause pain, blisters, and superficial wounds. Moreover, hyper- or hypopigmentation can arise during and immediately after these treatments and may be permanent. A major advantage of field-directed techniques is that they can be used to treat multiple contiguous lesions, including subclinical ones, i.e., sites of AK that cannot yet be seen or palpated. Such techniques include the topical application of agents in solution or in the form of a gel or cream, as well as photodynamic therapy (PDT). The common features of field-directed treatments are healing without scar and predominantly no more than transient local side effects such as pain, erythema, swelling, sterile pustules, erosions, and scabbing. Ten different preparations are now approved for field-directed treatment in Germany, differing in their mechanisms of action, galenic formulation, maximal area of application, duration of application, and side-effect profiles (Table 1). A hierarchical ranking of the available treatments is difficult, as direct comparison studies are generally lacking. Four field-directed treatments were recently compared directly with one another in an independently financed trial published in a high-ranking journal: 5-fluorouracil was found to yield the highest rate of healing at 12 months in patients with at least five lesions on the scalp (4).
The choice of a suitable treatment depends on patient-, lesion-, and treatment-specific factors (Table 2). Lesion-directed techniques can generally be carried out rapidly, but they are only effective over a small area. Field-directed techniques take a few days to months to apply and thus require high patient compliance. Some of them are not covered by health insurance in Germany (e.g., red-light PDT). Alongside the parameters listed in Table 2, the physician’s experience, the patient’s prior history, and the availability of treatments are further important factors that need to be considered in the choice of therapy.
Combinations of treatment approaches are reasonable and are being applied more and more frequently, e.g., field-directed treatment after lesion-directed treatment. For example, laser ablation can be carried out before PDT to remove especially thick hyperkeratotic lesions, thereby making the skin surface more permeable for cream application. Other studies have shown that the combination of imiquimod and PDT leads to significantly higher healing rates than monotherapy (5–7).
Cutaneous squamous cell carcinoma
The treatment options for cSCC include surgery, radiotherapy, and medication (Table 3, Figure 2).
Complete excision under histopathological guidance is the standard treatment of cSCC. There is no commonly accepted definition of an R0 resection; the desired distance from the edge of the tumor to the border of the resection varies in the literature from 0 to 6 mm (8). After resection and until the time of definitive histopathological confirmation, the wound should only be closed if the borders of the resection will remain clearly identifiable. For tumors less than 1 cm in size, shave-excision is an alternative to resection. In this situation, the diameter of the excised tissue should be no less than 5 mm to enable reliable histopathological examination (1). If the clinical diagnosis is unambiguously clear, excision can be carried out without prior biopsy. The risk factors for local recurrence and metastasis (Box 2) are also relevant to surgical planning, as one may want to consider wider safety margins or elective lymph node surgery (e.g., biopsy of a sentinel node) in patients at higher risk.
The technique of histopathological examination is what distinguishes conventional surgery from micrographically controlled surgery (MCS), also known as Mohs surgery (9). The latter generally involves 3D histology, i.e., once the tumor has been excised, the outer sides of the resection specimen are separately analyzed histologically to enable complete inspection of the three-dimensional edges of the resection (9). MCS allows the detection of outward extensions of the tumor with high sensitivity; consequently, the safety margin for excision can be kept relatively low. Although frozen sections are quicker to prepare, paraffin sections are superior for the detection of subclinical tumor extensions (9). MCS is to be distinguished from excision with a wide safety margin and lamellar sectioning of the specimen (the loaf-of-bread technique), in which the entire extent of the tumor is histologically examined (9). The safety margin for resection is not definitively laid down in the literature (1–4 mm, up to 50 mm under certain circumstances), but the risk of subtotal resection increases with the size of the specimen and in inverse relation to the safety margin (8). The local recurrence rate after MCS ranges from 0 to 33%, with rates of 2% to 8% reported in most studies. The local recurrence rate after resection with the loaf-of-bread technique ranges from 0% to 53%, with numbers of 2% to 13% most commonly reported (8). No method has yet been shown to be clearly superior to any other.
The identification and excision of one or more sentinel lymph nodes (sentinel lymph node biopsy, SLNB) is an option for minimally invasive lymph node diagnosis in order to detect occult metastasis while avoiding excessive lymphadenectomy. SLNB can be considered in patients with high-risk cSCC, particularly in the head and neck region, with its variable lymphatic flow. Despite high sensitivity (79%) and specificity (100%) and a negative predictive value of 96% (10), SLNB of one or more nodes has not been shown to result in significantly longer disease-specific overall or metastasis-free survival (11, 12), and it therefore cannot be generally recommended (1). Prophylactic lymphadenectomy should not be performed (1, 13). In the case of clinically or histologically apparent lymph node metastasis, therapeutic lymph node dissection should be performed, as this improves locoregional tumor control (8, 13). The extent of the therapeutic lymph node removal has not been precisely defined; if possible, selective functional resection should be carried out (1).
Resection is also the standard treatment for locoregional recurrence, as long as the conditions for local and general operability are met.
Although there have not been any prospective, randomized trials comparing primary radiotherapy with other local treatments, retrospective studies have shown a local tumor control rate of 94.0% at 5 years with radiotherapy alone (14). A prospective phase III trial compared radiation alone with radiochemotherapy for cSCC in the head and neck region. The additional administration of carboplatin was found not to have any additional effect; the rate of locoregional tumor control at 5 years was 83% after radiotherapy and 87% after radiochemotherapy, and the rates of 5-year overall survival were 76% and 79% (15).
Postoperative radiotherapy is indicated only in the presence of risk factors. These include R1 or R2 resection, a narrow resection margin (<2 mm), recurrent tumor, large tumor (>2 cm), deep tumor penetration (>4 mm), infiltration of adipose tissue, perineural sheath infiltration, and extensive lymphatic involvement (>1 lymph node, extension beyond capsule) (16–19). Postoperative radiotherapy should be performed after R1 or R2 resection or when the resection margin is <2 mm (1, 8, 17, 18, 20). The same holds for perineural sheath infiltration by tumor, although the extent of the infiltration is relevant here. If the infiltration is microscopic, the local control rate after surgery alone is 78% to 87%; if it is macroscopic, the local control rate after surgery is 50% to 55%, compared to 100% after postoperative radiotherapy in selected patients (19). Postoperative radiotherapy should also be performed in the case of extensive involvement of the cervical lymph nodes (> 1 lymph node, lymph node metastasis > 3 cm, extension beyond capsule, intraparotid lymph node involvement) (18, 21, 22). In a retrospective study, the local recurrence rate, 5-year disease-free survival rate, and overall survival rate after surgery alone were 55%, 34%, and 27%, respectively, while the corresponding rates after surgery and postoperative radiotherapy were 23%, 74%, and 66% (22). The procedure to be followed in the case of lymph node metastasis in the axillary or inguinal regions is analogous to the indication for postoperative radiotherapy in the head and neck region. Depending on the risk constellation, radiation doses ranging from 50 Gy (R1 resection, resection margin <2 mm) to 66 Gy (R2 resection) are recommended (18). For local or locoregional recurrences, the same criteria as in the primary situation apply with respect to the indication for postoperative radiotherapy (1).
Systemic drug treatment
Systemic drugs are given when local measures no longer suffice, e.g., in the case of a locally advanced lesion (usually after prior surgery and radiotherapy) or distant metastasis. In a systematic review of the literature from the years 1970 to 2011, Behshad et al. identified 28 studies (all with low-level evidence) including 119 patients with locally advanced cSCC who were treated with systemic drugs. In a large majority of cases, various chemotherapeutic agents were used either singly, in combination, or together with radiotherapy (23). The observed overall response rate was 72%, and the median response duration was 10.5 months.
In addition to chemotherapy, many publications have described the use of targeted therapies against the epidermal growth factor receptor (EGFR) to treat cSCC, but there have been only a few, uncontrolled prospective trials (24). In a trial of cetuximab on 36 patients, the response rate was 28%, and the median response duration was 6.8 months (25); in a trial of panitumumab on 16 patients, the response rate was 31%, and the median response duration was 6 months (26). In principle, EGFR blockers such as cetuximab can also be combined with chemotherapeutic drugs such as paclitaxel (27) or platinum derivatives (28), in a manner analogous to the treatment of mucosal squamous cell carcinoma.
Squamous cell carcinomas often express PD-L1 and contain tumor-infiltrating lymphocytes (29); thus, immune therapy targeted on PD-1 is another worthwhile approach. A single-armed trial of the anti-PD-1 antibody cemiplimab in 59 patients with metastatic squamous cell carcinoma yielded a response rate of 47%, and, at the time of assessment, most of these remissions had persisted longer than 6 months (30). The European Medicines Agency (EMA) has approved cemiplimab for the treatment of inoperably advanced or metastatic cSCC. Patients with inoperable cSCC are currently being recruited for a trial of cetuximab combined with the PD-L1 antibody avelumab. The PD-1 antibodies cemiplimab and pembrolizumab are being tested in placebo-controlled studies for the adjuvant treatment of patients after resection and radiotherapy of high-risk cSCC. It is particularly important that the treatment strategy for patients with cSCC should be designed on an individual basis in consideration of the patient’s age, comorbidities, and personal preferences.
Special considerations for immune-suppressed patients
Patients being treated with immune-suppressant drugs, particularly organ transplant recipients, have a markedly higher risk of developing AK and of progression of AK into invasive cSCC; these cSCC also show more aggressive growth than in the usual situation, with greatly elevated morbidity and mortality (31, 32). Organ transplant recipients have a 20- to 50-fold elevation of the risk of developing a non-melanocytic skin cancer compared to immune-competent persons (32). The same holds for patients who are immunocompromised because of an underlying illness, particularly chronic lymphocytic leukemia. Such patients should be informed early of the elevated risk and taught how to examine themselves; they should undergo dermatological surveillance examinations at intervals depending on the risk, and any suspect lesions should be diagnosed and treated as early as possible.
Data are available from randomized, controlled trials on the treatment of AK in organ transplant recipients with PDT combined with methyl aminolevulinic acid (MAL-PDT), ablative fractionated laser therapy (AFXL), diclofenac sodium 3% gel, imiquimod 5% cream, and 5-fluorouracil 5% cream: healing rates were highest with MAL-PDT and lowest with AFXL (33) (Table 1). Early diagnosis and surgical resection are determinative for the successful treatment of squamous cell carcinoma (34). Radiotherapy can be used to treat advanced lesions or those with a high risk of recurrence. The drug treatments listed here must be carefully considered because of their side effects. Immune therapy, in particular, can exacerbate an existing autoimmune disease or cause transplant rejection (35, 36).
As for iatrogenic immune suppression, multiple prospective, randomized trials carried out in kidney transplant recipients have unanimously shown that switching the immune-suppressant drug from a calcineurin inhibitor to an mTOR inhibitor in high-risk patients who have had epithelial skin tumors resected significantly lowers the risk of further skin tumors (37). This effect is greatest in patients who have had only one tumor resected, rather than two or more.
In two prospective, randomized, placebo-controlled trials on patients in whom epithelial skin tumors had been resected, the development of new cSCC was shown to be significantly less common after prophylactic treatment: one study concerned topical treatment with 5% 5-fluorouracil on the face for 2 to 4 weeks (38), and the other concerned the daily taking of 1000 mg nicotinic acid amide/vitamin B3 (39). In both trials, however, the effect was lost once the treatment was terminated. It follows that permanent nicotinic acid amide treatment can be considered for high-risk patients. Topical treatment with 5% 5-fluorouracil can be repeated depending on the clinical course and the development of new lesions. In organ transplant recipients, switching the immune-suppressant drug to an mTOR inhibitor can be considered.
The definition of actinic keratosis
Actinic keratosis (AK) consists of the intradermal proliferation of histologically atypical keratinocytes in an area of skin that has been chronically damaged by exposure to ultraviolet light.
The origin of cutaneous squamous cell carcinoma (cSCC)
In cSCC, the atypical keratinocytes break through the basal membrane; this can manifest itself with nodular growth. cSCC can arise de novo or on the basis of preexisting AK. The probability and speed of the transition from AK to cSCC is individual, highly variable, and unpredictable.
The age-standardized incidence rate of cSCC in Germany in 2010 to 2014 was 26.90 per 100 000 persons per year, 30% higher than the corresponding figure for 2005 to 2009.
Cumulative ultraviolet exposure is the main risk factor for AK and cSCC.
Treatment options for actinic keratosis
Actinic keratosis can be treated with lesion-directed and field-directed methods.
The choice of treatment
The choice of treatment depends on patient-, lesion-, and treatment-specific factors.
The gold standard
Complete excision is the gold standard treatment for cSCC.
The complete excision of cSCC should be histologically confirmed.
Radiotherapy should be performed if a tumor cannot be completely excised locally or is inoperable for medical reasons.
Postoperative radiotherapy is indicated if there are risk factors for local or locoregional recurrence.
The available types of drug therapy are chemotherapy, anti-EGFR therapy, and immune therapy targeted on PD-1.
Criteria for the choice of treatment
The treatment strategy for patients with cSCC should be designed on an individual basis in consideration of the patient’s age, comorbidities, and personal preferences.
The incidence and aggressiveness of AK and cSCC are higher in immune-suppressed patients.
The special case of the organ transplant recipient
In organ transplant recipients with AK or cSCC, switching the immune-suppressant drug to an mTOR inhibitor can be considered.
In organ transplant recipients, switching the immune suppressant drug to an mTOR inhibitor can be considered.
Conflict of interest statement
Prof. Gutzmer has served as a paid consultant for Roche, Bristol-Myers Squibb, Almirall Hermal, Amgen, Pierre Fabre, Merck Serono, Takeda, SUN, ASC, Incyte, Pfizer, Sanofi, and Novartis. He has received lecture honoraria from Roche, Bristol-Myers Squibb, MSD, Novartis, Amgen, Pierre Fabre, Merck-Serono, Almirall, AstraZeneca, Sanofi, and SUN. He has received reimbursement of congress participation fees and travel expenses from Merck-Serono, Pierre Fabre, BMS, Roche, and SUN. He has received funding from Novartis, Amgen, Merck-Serono, Pfizer, and Johnson & Johnson for a research project that he initiated.
Prof. Wiegand has served as a paid consultant for Bristol-Myers Squibb and MSD. She has received lecture honoraria from Astra Zeneca, MSD, Merck-Serono, and Bristol-Myers Squibb. She has received reimbursement of travel and accommodation expenses from Astra Zeneca, MSD, and Bristol-Myers Squibb.
PD Wermker has served as a paid member of an Advisory Board for Bristol-Myers Squibb.
Dr. Heppt has served as a paid consultant for Sanofi-Aventis.
Prof. Berking has served as a paid consultant for Almirall Hermal, Galderma, Leo Pharma, MSD, and Sanofi-Aventis. She has received lecture honoraria from Leo Pharma and Galderma. She has received funding from Leo Pharma for a research project that she initiated and third-party research funding from Biofrontera.
Prof. Kölbl states that he has no conflict of interest.
Manuscript submitted on 29 March 2019, revised version accepted on
4 July 2019
Translated from the original German by Ethan Taub, M.D.
Prof. Dr. med. Ralf Gutzmer
Klinik für Dermatologie, Allergologie und Venerologie
Medizinische Hochschule Hannover (MHH)
Carl Neuberg Str. 1
30625 Hannover, Germany
Cite this as:
Gutzmer R, Wiegand S, Kölbl O, Wermker K, Heppt M, Berking C:
Actinic keratosis and cutaneous squamous carcinoma—treatment options.
Dtsch Arztebl Int 2019; 116: 616–26; DOI: 10.3238/arztebl.2019.0616
For eReferences please refer to:
Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig:
Prof. Dr. med.
Department of Radiotherapy, University Hospital Regensburg: Prof. Dr. med. Oliver Kölbl
Department of Oromaxillofacial, Plastic and Esthetic Surgery, Osnabrück Hospital GmbH, Osnabrück: PD Dr. med. Dr. med. dent. Kai Wermker
Department of Dermatology and Allergology, University Hospital (LMU), Munich: Dr. med. Markus Heppt, Prof. Dr. med. Carola Berking
|1.||Deutsche Krebsgesellschaft DKg, AWMF: S3-Leitlinie Aktinische Keratose und Plattenepithelkarzinom der Haut. Langversion 1.0. www.awmf.org/uploads/tx_szleitlinien/032–022OLk_S3_Aktinische_Keratosen-Plattenepithelkarzinom-PEK_2019–07.pdf (last accessed on 3 August 2019).|
|2.||Werner RN, Sammain A, Erdmann R, Hartmann V, Stockfleth E, Nast A: The natural history of actinic keratosis: a systematic review. Br J Dermatol 2013; 169: 502–18 CrossRef MEDLINE|
|3.||Hillen U, Ulrich M, Alter M, et al.: [Cutaneous squamous cell carcinoma: a review with consideration of special patient groups]. Hautarzt 2014; 65: 590–9 CrossRef MEDLINE|
|4.||Jansen MHE, Kessels J, Nelemans PJ, et al.: Randomized trial of four treatment approaches for actinic keratosis. N Engl J Med 2019; 380: 935–46 CrossRef MEDLINE|
|5.||Heppt MV, Steeb T, Leiter U, Berking C: Efficacy of photodynamic therapy combined with topical interventions for the treatment of actinic keratosis: a meta-analysis. J Eur Acad Dermatol Venereol 2019; 33: 863–73 CrossRef MEDLINE|
|6.||Heppt MV, Steeb T, Ruzicka T, Berking C: Cryosurgery combined with topical interventions for actinic keratosis: a systematic review and meta-analysis. Br J Dermatol 2019; 180: 740–8 CrossRef MEDLINE|
|7.||Steeb T, Schlager JG, Kohl C, Ruzicka T, Heppt MV, Berking C: Laser-assisted photodynamic therapy for actinic keratosis: a systematic review and meta-analysis. J Am Acad Dermatol 2019; 80: 947–56 CrossRef MEDLINE|
|8.||Stratigos A, Garbe C, Lebbe C, et al.: Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline. Eur J Cancer 2015; 51: 1989–2007 CrossRef MEDLINE|
|9.||Loser CR, Rompel R, Mohrle M, et al.: S1 guideline: microscopically controlled surgery. J Dtsch Dermatol Ges 2015; 13: 942–51 CrossRef MEDLINE|
|10.||Allen JE, Stolle LB: Utility of sentinel node biopsy in patients with high-risk cutaneous squamous cell carcinoma. Eur J Surg Oncol 2015; 41: 197–200 CrossRef MEDLINE|
|11.||Leiter U, Gutzmer R, Alter M, et al.: [Cutaneous squamous cell carcinoma]. Hautarzt 2016; 67: 857–66 CrossRef MEDLINE|
|12.||Krediet JT, Beyer M, Lenz K, et al.: Sentinel lymph node biopsy and risk factors for predicting metastasis in cutaneous squamous cell carcinoma. Br J Dermatol 2015; 172: 1029–36 CrossRef MEDLINE|
|13.||Newlands C, Currie R, Memon A, Whitaker S, Woolford T: Non-melanoma skin cancer: United Kingdom national multidisciplinary guidelines. J Laryngol Otol 2016; 130: 125–32 CrossRef MEDLINE PubMed Central|
|14.||Mendenhall WM, Amdur RJ, Hinerman RW, et al.: Skin cancer of the head and neck with perineural invasion. Am J Clin Oncol 2007; 30: 93–6 CrossRef MEDLINE|
|15.||Porceddu SV, Bressel M, Poulsen MG, et al.: Postoperative concurrent chemoradiotherapy versus postoperative radiotherapy in high-risk cutaneous squamous cell carcinoma of the head and neck: the randomized phase III TROG 05.01 trial. J Clin Oncol 2018; 36: 1275–83 CrossRef MEDLINE|
|16.||Erkan S, Savundra JM, Wood B, Acharya AN, Rajan GP: Clinical perineural invasion of the trigeminal and facial nerves in cutaneous head and neck squamous cell carcinoma: outcomes and prognostic implications of multimodality and salvage treatment. Head Neck 2017; 39: 1280–6 CrossRef MEDLINE|
|17.||Jambusaria-Pahlajani A, Miller CJ, Quon H, Smith N, Klein RQ, Schmults CD: Surgical monotherapy versus surgery plus adjuvant radiotherapy in high-risk cutaneous squamous cell carcinoma: a systematic review of outcomes. Dermatol Surg 2009; 35: 574–85 CrossRef MEDLINE|
|18.||Veness MJ: Treatment recommendations in patients diagnosed with high-risk cutaneous squamous cell carcinoma. Australas Radiol 2005; 49: 365–76 CrossRef MEDLINE|
|19.||Han A, Ratner D: What is the role of adjuvant radiotherapy in the treatment of cutaneous squamous cell carcinoma with perineural invasion? Cancer 2007; 109: 1053–9 CrossRef MEDLINE|
|20.||Tanvetyanon T, Padhya T, McCaffrey J, et al.: Postoperative concurrent chemotherapy and radiotherapy for high-risk cutaneous squamous cell carcinoma of the head and neck. Head Neck 2015; 37: 840–5 CrossRef MEDLINE|
|21.||Amoils M, Lee CS, Sunwoo J, et al.: Node-positive cutaneous squamous cell carcinoma of the head and neck: survival, high-risk features, and adjuvant chemoradiotherapy outcomes. Head Neck 2017; 39: 881–5 CrossRef MEDLINE|
|22.||Wang JT, Palme CE, Morgan GJ, Gebski V, Wang AY, Veness MJ: Predictors of outcome in patients with metastatic cutaneous head and neck squamous cell carcinoma involving cervical lymph nodes: improved survival with the addition of adjuvant radiotherapy. Head Neck 2012; 34: 1524–8 CrossRef MEDLINE|
|23.||Behshad R, Garcia-Zuazaga J, Bordeaux JS: Systemic treatment of locally advanced nonmetastatic cutaneous squamous cell carcinoma: a review of the literature. Br J Dermatol 2011; 165: 1169–77 CrossRef MEDLINE|
|24.||Alter M, Satzger I, Mattern A, Kapp A, Gutzmer R: Treatment of advanced cutaneous squamous cell carcinomas with epidermal growth factor receptor inhibitors. Dermatology 2013; 227: 289–94 CrossRef MEDLINE|
|25.||Maubec E, Petrow P, Scheer-Senyarich I, et al.: Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol 2011; 29: 3419–26 CrossRef MEDLINE|
|26.||Foote MC, McGrath M, Guminski A, et al.: Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma. Ann Oncol 2014; 25: 2047–52 CrossRef MEDLINE|
|27.||Hitt R, Irigoyen A, Cortes-Funes H, et al.: Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Ann Oncol 2012; 23: 1016–22 CrossRef MEDLINE|
|28.||Vermorken JB, Mesia R, Rivera F, et al.: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116–27 CrossRef MEDLINE|
|29.||Schaper K, Kother B, Hesse K, Satzger I, Gutzmer R: The pattern and clinicopathological correlates of programmed death-ligand 1 expression in cutaneous squamous cell carcinoma. Br J Dermatol 2017; 176: 1354–6 CrossRef MEDLINE|
|30.||Migden MR, Rischin D, Schmults CD, et al.: PD-1-Blockade with Cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 2018; 379: 341–51 CrossRef MEDLINE|
|31.||Euvrard S, Kanitakis J, Claudy A: Skin cancers after organ transplantation. N Engl J Med 2003; 348: 1681–91 CrossRef MEDLINE|
|32.||Ulrich C, Arnold R, Frei U, Hetzer R, Neuhaus P, Stockfleth E: Skin changes following organ transplantation: an interdisciplinary challenge. Dtsch Arztebl Int 2014; 111: 188–94 VOLLTEXT|
|33.||Heppt MV, Steeb T, Niesert AC, et al.: Local interventions for actinic keratosis in organ transplant recipients: a systematic review. Br J Dermatol 2019; 180: 43–50 CrossRef MEDLINE|
|34.||Cheng JY, Li FY, Ko CJ, Colegio OR: Cutaneous squamous cell carcinomas in solid organ transplant recipients compared with immunocompetent patients. JAMA Dermatol 2018; 154: 60–6 CrossRef MEDLINE PubMed Central|
|35.||Tio M, Rai R, Ezeoke OM, et al.: Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection. Eur J Cancer 2018; 104: 137–44 CrossRef MEDLINE|
|36.||Gutzmer R, Koop A, Meier F, et al.: Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity. Eur J Cancer 2017; 75: 24–32 CrossRef MEDLINE|
|37.||Alter M, Satzger I, Schrem H, Kaltenborn A, Kapp A, Gutzmer R: Non-melanoma skin cancer is reduced after switch of immunosuppression to mTOR-inhibitors in organ transplant recipients. J Dtsch Dermatol Ges 2014; 12: 480–8 CrossRef MEDLINE|
|38.||Weinstock MA, Thwin SS, Siegel JA, et al.: Chemoprevention of basal and squamous cell carcinoma with a single course of fluorouracil, 5%, cream: a randomized clinical trial. JAMA Dermatol 2018; 154: 167–74 CrossRef MEDLINE PubMed Central|
|39.||Chen AC, Martin AJ, Choy B, et al.: A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med 2015; 373: 1618–26 CrossRef MEDLINE|
|40.||Brantsch KD, Meisner C, Schonfisch B, et al.: Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol 2008; 9: 713–20 CrossRef MEDLINE|
|e1.||Wermker K, Belok F, Schipmann S, Klein M, Schulze HJ, Hallermann C: Prediction model for lymph node metastasis and recommendations for elective neck dissection in lip cancer. J Craniomaxillofac Surg 2015; 43: 545–52 CrossRef MEDLINE|
|e2.||Wermker K, Kluwig J, Schipmann S, Klein M, Schulze HJ, Hallermann C: Prediction score for lymph node metastasis from cutaneous squamous cell carcinoma of the external ear. Eur J Surg Oncol 2015; 41: 128–35 CrossRef MEDLINE|
|e3.||Foley P, Merlin K, Cumming S, et al.: A comparison of cryotherapy and imiquimod for treatment of actinic keratoses: lesion clearance, safety, and skin quality outcomes. J Drugs Dermatol 2011; 10: 1432–8.|
|e4.||Krawtchenko N, Roewert-Huber J, Ulrich M, Mann I, Sterry W, Stockfleth E: A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol 2007; 157(Suppl 2): 34–40 CrossRef MEDLINE|
|e5.||Simon JC, Dominicus R, Karl L, Rodriguez R, Willers C, Dirschka T: A prospective randomized exploratory study comparing the efficacy of once-daily topical 0.5% 5-fluorouracil in combination with 10.0% salicylic acid (5-FU/SA) vs. cryosurgery for the treatment of hyperkeratotic actinic keratosis. J Eur Acad Dermatol Venereol 2015; 29: 881–9 CrossRef MEDLINE|
|e6.||Zane C, Facchinetti E, Rossi MT, Specchia C, Ortel B, Calzavara-Pinton P: Cryotherapy is preferable to ablative CO2 laser for the treatment of isolated actinic keratoses of the face and scalp: a randomized clinical trial. Br J Dermatol 2014; 170: 1114–21 CrossRef MEDLINE|
|e7.||Kaufmann R, Spelman L, Weightman W, et al.: Multicentre intraindividual randomized trial of topical methyl aminolaevulinate-photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities. Br J Dermatol 2008; 158: 994–9 CrossRef MEDLINE|
|e8.||Morton C, Campbell S, Gupta G, et al.: Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study. Br J Dermatol 2006; 155: 1029–36 CrossRef MEDLINE|
|e9.||Ostertag JU, Quaedvlieg PJ, van der Geer S, et al.: A clinical comparison and long-term follow-up of topical 5-fluorouracil versus laser resurfacing in the treatment of widespread actinic keratoses. Lasers Surg Med 2006; 38: 731–9 CrossRef MEDLINE|
|e10.||McEwan LE, Smith JG: Topical diclofenac/hyaluronic acid gel in the treatment of solar keratoses. Australas J Dermatol 1997; 38: 187–9 CrossRef MEDLINE|
|e11.||Pflugfelder A, Welter AK, Leiter U, et al.: Open label randomized study comparing 3 months vs. 6 months treatment of actinic keratoses with 3% diclofenac in 2.5% hyaluronic acid gel: a trial of the German Dermatologic Cooperative Oncology Group. J Eur Acad Dermatol Venereol 2012; 26: 48–53 CrossRef MEDLINE|
|e12.||Stockfleth E, Kerl H, Zwingers T, Willers C: Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol 2011; 165: 1101–8 CrossRef MEDLINE|
|e13.||Ulrich C, Johannsen A, Rowert-Huber J, Ulrich M, Sterry W, Stockfleth E: Results of a randomized, placebo-controlled safety and efficacy study of topical diclofenac 3% gel in organ transplant patients with multiple actinic keratoses. Eur J Dermatol 2010; 20: 482–8 CrossRef MEDLINE|
|e14.||Wolf JE, Jr., Taylor JR, Tschen E, Kang S: Topical 3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol 2001; 40: 709–13 CrossRef MEDLINE|
|e15.||Zane C, Facchinetti E, Rossi MT, Specchia C, Calzavara-Pinton PG: A randomized clinical trial of photodynamic therapy with methyl aminolaevulinate vs. diclofenac 3% plus hyaluronic acid gel for the treatment of multiple actinic keratoses of the face and scalp. Br J Dermatol 2014; 170: 1143–50 CrossRef MEDLINE|
|e16.||Gebauer K, Brown P, Varigos G: Topical diclofenac in hyaluronan gel for the treatment of solar keratoses. Australas J Dermatol 2003; 44: 40–3 CrossRef|
|e17.||Rivers JK, Arlette J, Shear N, Guenther L, Carey W, Poulin Y: Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel. Br J Dermatol 2002; 146: 94–100 CrossRef MEDLINE|
|e18.||Stockfleth E, Zwingers T, Willers C: Recurrence rates and patient assessed outcomes of 0.5% 5-fluorouracil in combination with salicylic acid treating actinic keratoses. Eur J Dermatol 2012; 22: 370–4 CrossRef MEDLINE|
|e19.||Pomerantz H, Hogan D, Eilers D, et al.: Long-term efficacy of topical fluorouracil cream, 5%, for treating actinic keratosis: a randomized clinical trial. JAMA Dermatol 2015; 151: 952–60 CrossRef MEDLINE|
|e20.||Tanghetti E, Werschler P: Comparison of 5% 5-fluorouracil cream and 5% imiquimod cream in the management of actinic keratoses on the face and scalp. J Drugs Dermatol 2007; 6: 144–7.|
|e21.||Loven K, Stein L, Furst K, Levy S: Evaluation of the efficacy and tolerability of 0.5% fluorouracil cream and 5% fluorouracil cream applied to each side of the face in patients with actinic keratosis. Clin Ther 2002; 24: 990–1000 CrossRef|
|e22.||Garbe C, Basset-Seguin N, Poulin Y, et al.: Efficacy and safety of follow-up field treatment of actinic keratosis with ingenol mebutate 0.015% gel: a randomized, controlled 12-month study. Br J Dermatol 2016; 174: 505–13 CrossRef MEDLINE|
|e23.||Moggio E, Arisi M, Zane C, Calzavara-Pinton I, Calzavara-Pinton P: A randomized split-face clinical trial analyzing daylight photodynamic therapy with methyl aminolaevulinate vs ingenol mebutate gel for the treatment of multiple actinic keratoses of the face and the scalp. Photodiagnosis Photodyn Ther 2016; 16: 161–5 CrossRef MEDLINE|
|e24.||Zane C, Fabiano A, Arisi M, Calzavara-Pinton P: A randomized split-face clinical trial of photodynamic therapy with methyl aminolevulinate versus ingenol mebutate gel for the treatment of multiple actinic keratoses of the face and scalp. Dermatology 2016; 232: 472–7 CrossRef MEDLINE|
|e25.||Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, Berman B: Ingenol mebutate gel for actinic keratosis. N Engl J Med 2012; 366: 1010–9 CrossRef MEDLINE|
|e26.||Lebwohl M, Shumack S, Stein Gold L, Melgaard A, Larsson T, Tyring SK: Long-term follow-up study of ingenol mebutate gel for the treatment of actinic keratoses. JAMA Dermatol 2013; 149: 666–70 CrossRef MEDLINE|
|e27.||Sinnya S, Tan JM, Prow TW, et al.: A randomized, phase IIa exploratory trial to assess the safety and preliminary efficacy of LEO 43204 in patients with actinic keratosis. Br J Dermatol 2016; 174: 305–11 CrossRef MEDLINE|
|e28.||Anderson L, Schmieder GJ, Werschler WP, et al.: Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dermatol 2009; 60: 934–43 CrossRef MEDLINE|
|e29.||Hanke CW, Beer KR, Stockfleth E, Wu J, Rosen T, Levy S: Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles. J Am Acad Dermatol 2010; 62: 573–81 CrossRef MEDLINE|
|e30.||Swanson N, Abramovits W, Berman B, Kulp J, Rigel DS, Levy S: Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol 2010; 62: 582–90 CrossRef MEDLINE|
|e31.||Alomar A, Bichel J, McRae S: Vehicle-controlled, randomized, double-blind study to assess safety and efficacy of imiquimod 5% cream applied once daily 3 days per week in one or two courses of treatment of actinic keratoses on the head. Br J Dermatol 2007; 157: 133–41 CrossRef MEDLINE|
|e32.||Chen K, Yap LM, Marks R, Shumack S: Short-course therapy with imiquimod 5% cream for solar keratoses: a randomized controlled trial. Australas J Dermatol 2003; 44: 250–5 CrossRef|
|e33.||Jorizzo J, Dinehart S, Matheson R, et al.: Vehicle-controlled, double-blind, randomized study of imiquimod 5% cream applied 3 days per week in one or two courses of treatment for actinic keratoses on the head. J Am Acad Dermatol 2007; 57: 265–8 CrossRef MEDLINE|
|e34.||Korman N, Moy R, Ling M, et al.: Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol 2005; 141: 467–73 CrossRef MEDLINE|
|e35.||Kose O, Koc E, Erbil AH, Caliskan E, Kurumlu Z: Comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% imiquimod cream in the treatment of actinic keratosis. J Dermatolog Treat 2008; 19: 159–63 CrossRef MEDLINE|
|e36.||Lebwohl M, Dinehart S, Whiting D, et al.: Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol 2004; 50: 714–21 CrossRef MEDLINE|
|e37.||Ooi T, Barnetson RS, Zhuang L, et al.: Imiquimod-induced regression of actinic keratosis is associated with infiltration by T lymphocytes and dendritic cells: a randomized controlled trial. Br J Dermatol 2006; 154: 72–8 CrossRef MEDLINE|
|e38.||Stockfleth E, Meyer T, Benninghoff B, et al.: A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol 2002; 138: 1498–502 CrossRef MEDLINE|
|e39.||Szeimies RM, Gerritsen MJ, Gupta G, et al.: Imiquimod 5% cream for the treatment of actinic keratosis: results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J Am Acad Dermatol 2004; 51: 547–55 CrossRef MEDLINE|
|e40.||Ulrich C, Bichel J, Euvrard S, et al.: Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients. Br J Dermatol 2007; 157(Suppl 2): 25–31 CrossRef MEDLINE PubMed Central|
|e41.||Smith S, Piacquadio D, Morhenn V, Atkin D, Fitzpatrick R: Short incubation PDT versus 5-FU in treating actinic keratoses. J Drugs Dermatol 2003; 2: 629–35.|
|e42.||Szeimies RM, Radny P, Sebastian M, et al.: Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a prospective, randomized, double-blind, placebo-controlled phase III study. Br J Dermatol 2010; 163: 386–94 CrossRef MEDLINE|
|e43.||Dirschka T, Radny P, Dominicus R, et al.: Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo. Br J Dermatol 2012; 166: 137–46 CrossRef MEDLINE|
|e44.||Holzer G, Pinkowicz A, Radakovic S, Schmidt JB, Tanew A: Randomized controlled trial comparing 35% trichloroacetic acid peel and 5-aminolaevulinic acid photodynamic therapy for treating multiple actinic keratosis. Br J Dermatol 2017; 176: 1155–61 CrossRef|
|e45.||Jeffes EW, McCullough JL, Weinstein GD, Kaplan R, Glazer SD, Taylor JR: Photodynamic therapy of actinic keratoses with topical aminolaevulinic acid hydrochloride and fluorescent blue light. J Am Acad Dermatol 2001; 45: 96–104 CrossRef MEDLINE|
|e46.||Moloney FJ, Collins P: Randomized, double-blind, prospective study to compare topical 5-aminolaevulinic acid methylester with topical 5-aminolevulinic acid photodynamic therapy for extensive scalp actinic keratosis. Br J Dermatol 2007; 157: 87–91 CrossRef MEDLINE|
|e47.||Piacquadio DJ, Chen DM, Farber HF, et al.: Photodynamic therapy with aminolevulinic acid topical solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp: investigator-blinded, phase 3, multicenter trials. Arch Dermatol 2004; 140: 41–6 CrossRef MEDLINE|
|e48.||Reinhold U, Dirschka T, Ostendorf R, et al.: A randomized, double-blind, phase III, multicentre study to evaluate the safety and efficacy of BF-200 ALA (Ameluz(®) ) vs. placebo in the field-directed treatment of mild-to-moderate actinic keratosis with photodynamic therapy (PDT) when using the BF-RhodoLED(®) lamp. Br J Dermatol 2016; 175: 696–705 CrossRef MEDLINE|
|e49.||Pariser DM, Lowe NJ, Stewart DM, et al.: Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial. J Am Acad Dermatol 2003; 48: 227–32 CrossRef MEDLINE|
|e50.||Pariser D, Loss R, Jarratt M, et al.: Topical methyl-aminolevulinate photodynamic therapy using red light-emitting diode light for treatment of multiple actinic keratoses: a randomized, double-blind, placebo-controlled study. J Am Acad Dermatol 2008; 59: 569–76 CrossRef MEDLINE|
|e51.||Szeimies RM, Matheson RT, Davis SA, et al.: Topical methyl aminolevulinate photodynamic therapy using red light-emitting diode light for multiple actinic keratoses: a randomized study. Dermatol Surg 2009; 35: 586–92 CrossRef MEDLINE|
|e52.||Dragieva G, Prinz BM, Hafner J, et al.: A randomized controlled clinical trial of topical photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratoses in transplant recipients. Br J Dermatol 2004; 151: 196–200 CrossRef MEDLINE|
|e53.||Neittaanmaki-Perttu N, Gronroos M, Karppinen T, Snellman E, Rissanen P: Photodynamic therapy for actinic keratoses: a randomized prospective non-sponsored cost-effectiveness study of daylight-mediated treatment compared with light-emitting diode treatment. Acta Derm Venereol 2016; 96: 241–4 CrossRef MEDLINE|
|e54.||Wiegell SR, Haedersdal M, Eriksen P, Wulf HC: Photodynamic therapy of actinic keratoses with 8% and 16% methyl aminolaevulinate and home-based daylight exposure: a double-blinded randomized clinical trial. Br J Dermatol 2009; 160: 1308–14 CrossRef MEDLINE|
|e55.||Wiegell SR, Fabricius S, Stender IM, et al.: A randomized, multicentre study of directed daylight exposure times of 1(1/2) vs. 2(1/2) h in daylight-mediated photodynamic therapy with methyl aminolaevulinate in patients with multiple thin actinic keratoses of the face and scalp. Br J Dermatol 2011; 164: 1083–90 CrossRef MEDLINE|
|e56.||Chren MM, Linos E, Torres JS, Stuart SE, Parvataneni R, Boscardin WJ: Tumor recurrence 5 years after treatment of cutaneous basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol 2013; 133: 1188–96 CrossRef MEDLINEPubMed Central|
|e57.||Lansbury L, Bath-Hextall F, Perkins W, Stanton W, Leonardi-Bee J: Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies. BMJ 2013; 347: f6153 CrossRef MEDLINE PubMed Central|
|e58.||Brodland DG, Zitelli JA: Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 1992; 27: 241–8 CrossRef|
|e59.||Bertino G, Sersa G, De Terlizzi F, et al.: European Research on Electrochemotherapy in Head and Neck Cancer (EURECA) project: results of the treatment of skin cancer. Eur J Cancer 2016; 63: 41–52 CrossRef MEDLINE|
|e60.||Guminski A, Lim AM, Khushalani NI, et al.: Phase 2 study of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with metastatic cutaneous squamous cell carcinoma (mCSCC; Group 1): 12-month follow-up. J Clin Oncol 2019; 37: 9526 CrossRef|
|e61.||Migden MR, Khushalani NI, Chang AL, et al.: Primary analysis of phase 2 results of cemiplimab, a human monoclonal anti–PD-1, in patients with locally advanced cutaneous squamous cell carcinoma. J Clin Oncol 2019; 37: 6015 CrossRef|
|e62.||Maubec E, Boubaya M, Petrow P, et al.: Pembrolizumab as first-line therapy in patients with unresectable cutaneous squamous cell carcinoma (cSCC): Phase 2 results from CARSKIN. J Clin Oncol 2019; 37: 9547 CrossRef|
|e63.||Hillen U, Leiter U, Haase S, 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; 96: 34–43 CrossRef MEDLINE|
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