European Journal of Cancer 193 (2023) 113252

Available online at [Link]

j o u rn a l h o mep a ge : w ww.e j cance r .c om

Original Research

European consensus-based interdisciplinary guideline

for invasive cutaneous squamous cell carcinoma: Part 2. ]]
]]]]]]
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Treatment–Update 2023
⁎
Alexander J. Stratigos a, , Claus Garbe b, Clio Dessinioti a,
Celeste Lebbe c, Alexander van Akkooi d,e,f, Veronique Bataille g,
Lars Bastholt h, Brigitte Dreno i, Reinhard Dummer j,
Maria Concetta Fargnoli k, Ana Maria Forsea l,
Catherine A. Harwood m, Axel Hauschild n, Christoph Hoeller o,
Lidija Kandolf-Sekulovic p, Roland Kaufmann q,
Nicole WJ Kelleners-Smeets r,s, Aimilios Lallas t, Ulrike Leiter b,
Josep Malvehy u, Veronique del Marmol v, David Moreno-Ramirez w,
Giovanni Pellacani x, Ketty Peris y,z, Philippe Saiag aa,
Luca Tagliaferri ab, Myrto Trakatelli ac, Dimitrios Ioannides t,
Ricardo Vieira ad, Iris Zalaudek ae, Petr Arenberger af,
Alexander M.M. Eggermont ag,ah, Martin Röcken b,
Jean-Jacques Grob ai, Paul Lorigan aj,ak, On behalf of EADO, EDF,
ESTRO, UEMS, EADV and EORTC 1

a
First Department of Dermatology-Venereology, National and Kapodistrian University of Athens, Andreas Sygros
Hospital, Athens, Greece
b
Centre for Dermatooncology, Department of Dermatology, Eberhard Karls University, Tuebingen, Germany
c
Université Paris Cite, Dermato-Oncology AP-HP Hôpital Saint Louis, Cancer Institute APHP. Nord-Université Paris
Cite, INSERM U976, Paris, France
d
Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
e
Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
f
Melanoma Institute Australia, Sydney, New South Wales, Australia
g
Mount Vernon Cancer Centre, East and North NHS Trust, Northwood, UK
h
Department of Oncology, Odense University Hospital, Odense, Denmark

⁎
Corresponding author: First Department of Dermatology-Venereology, National and Kapodistrian University of Athens, Andreas Sygros
Hospital, Athens, Greece.
E-mail address: alstrat2@[Link] (A.J. Stratigos).
1
EADO, European Association of Dermato-Oncology; EDF, European Dermatology Forum; ESTRO, European Society for Radiotherapy
and Oncology; UEMS, European Union of Medical Specialists (Union Européenne des Médecins Spécialistes); EADV, European Academy of
Dermatology and Venereology; EORTC, European Organization for Research and Treatment of Cancer.

[Link]
0959-8049/© 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license ([Link]
[Link]/licenses/by-nc-nd/4.0/).
2 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252

i
Nantes Université, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302/
EMR6001, Nantes, France
j
Skin Cancer Centre at University Hospital, Zurich, Switzerland
k
Dermatology Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
l
Carol Davila University of Medicine and Pharmacy Bucharest, Department of Oncologic Dermatology, Elias University
Hospital Bucharest, Bucharest, Romania
m
Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and
Dentistry, Queen Mary University of London, London, UK
n
Department of Dermatology, University Hospital (UKSH), Kiel, Germany
o
Department of Dermatology, Medical University of Vienna, Vienna, Austria
p
Department of Dermatology, Medical Faculty, Military Medical Academy, Belgrade, Serbia
q
Department of Dermatology, Venereology and Allergology, Frankfurt University Hospital, Frankfurt, Germany
r
GROW-School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands
s
Department of Dermatology, Maastricht University Medical Centre+, Maastricht University, Maastricht,
the Netherlands
t
First Department of Dermatology, Aristotle University, Thessaloniki, Greece
u
Dermatology Department of Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBER de enfermedades
raras, Instituto Carlos III, Barcelona, Spain
v
Department of Dermatology, University Hospital Erasme, Université Libre de Bruxelles, Brussels, Belgium
w
Department of Medical and Surgical Dermatology Service, Hospital Universitario Virgen Macarena, Sevilla, Spain
x
Dermatology Unit, University of Rome La Sapienza, Rome, Italy
y
UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche,
Fondazione Policlinico Universitario A. Gemelli–IRCCS, Rome, Italy
z
Dermatologia, Università Cattolica del Sacro Cuore, Rome, Italy
aa
Department of General and Oncologic Dermatology, Ambroise-Paré hospital, APHP, and EA 4340 ‘Biomarkers in
Cancerology and Hemato-oncology’, UVSQ, Université Paris-Saclay, Boulogne-Billancourt, France
ab
UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia,
Fondazione Policlinico Universitario A, Gemelli IRCCS, Rome, Italy
ac
Department of Dermatology, Papageorgiou Hospital, Aristotle University Department of Medicine, Thessaloniki,
Greece
ad
Department of Dermatology, Coimbra Hospital and University Centre, Coimbra, Portugal
ae
Department of Dermatology, University of Trieste, Trieste, Italy
af
Department of Dermatovenereology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
ag
University Medical Center Utrecht and Princess Máxima Center, Utrecht, the Netherlands
ah
Comprehensive Cancer Center Munich, Technical University Munich and Ludwig Maximilian University, Munich,
Germany
ai
Aix Marseille University, APHM Hospital, Marseille, France
aj
Division of Cancer Sciences, University of Manchester, Manchester, UK
ak
Department of Medical Oncology, Christie NHS Foundation Trust, Manchester, UK

Received 18 July 2023; Accepted 18 July 2023

Available online 28 July 2023

KEYWORDS Abstract In order to update recommendations on treatment, supportive care, education,

Cutaneous squamous and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a mul­
cell carcinoma; tidisciplinary panel of experts from the European Association of Dermato-Oncology
Locally advanced; (EADO), the European Dermatology Forum (EDF), the European Society for Radiotherapy
Metastatic; and Oncology (ESTRO), the European Union of Medical Specialists (UEMS), the European
Treatment; Academy of Dermatology and Venereology (EADV), and the European Organisation of
Surgical excision; Research and Treatment of Cancer (EORTC) was formed. Recommendations were based on
Radiotherapy; an evidence-based literature review, guidelines, and expert consensus. Treatment re­
Adjuvant; commendations are presented for common primary cSCC (low risk, high risk), locally ad­
Anti-PD-1 antibody; vanced cSCC, regional metastatic cSCC (operable or inoperable), and distant metastatic
Cemiplimab; cSCC. For common primary cSCC, the first-line treatment is surgical excision with post­
Follow-up operative margin assessment or micrographically controlled surgery. Achieving clear surgical
margins is the most important treatment consideration for patients with cSCCs amenable to
surgery. Regarding adjuvant radiotherapy for patients with high-risk localised cSCC with
clear surgical margins, current evidence has not shown significant benefit for those with at
least one high-risk factor. Radiotherapy should be considered as the primary treatment for
non-surgical candidates/tumours. For cSCC with cytologically or histologically confirmed
regional nodal metastasis, lymph node dissection is recommended. For patients with meta­
static or locally advanced cSCC who are not candidates for curative surgery or radiotherapy,
anti-PD-1 agents are the first-line systemic treatment, with cemiplimab being the first
 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252 3

approved systemic agent for advanced cSCC by the Food and Drugs Administration/
European Medicines Agency. Second-line systemic treatments for advanced cSCC, include
epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or
radiotherapy. Multidisciplinary board decisions are mandatory for all patients with advanced
cSCC, considering the risks of toxicity, the age and frailty of patients, and co-morbidities,
including immunosuppression. Patients should be engaged in informed, shared decision-
making on management and be provided with the best supportive care to improve symptom
management and quality of life. The frequency of follow-up visits and investigations for
subsequent new cSCC depends on underlying risk characteristics.
© 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC
BY-NC-ND license ([Link]

1. Information about the guideline The guideline manuscripts were additionally reviewed
by reviewers from each participating society, who were
The European Interdisciplinary Guidelines on invasive not included as authors of the guidelines.
squamous cell carcinoma of the skin were written as a
uniform text and then published in two separate but 1.1. Consensus building process
integral parts: part 1 on definitions, epidemiology,
etiopathogenesis, diagnosis, risk classification, sta­
The meeting was held in Rome, Italy, on 25th
ging, and prevention and part 2 on treatments, sup­ November 2022. A structured consensus process was
portive care, communication with the patient, and used to discuss and agree upon, with final outcomes: (1)
follow-up. Information about the Guidelines is detailed
the approval of the text and (2) a consensus rate of
in Stratigos et al. Part 1. 2023., including the informa­ agreement of at least 80%, for recommendations pro­
tion about societies in charge, financing of the guide­ vided in structured boxes and the figure. Voting of the
lines, scope, target population, objectives, and
recommendations included the selection of ‘Agree,’
formulation of sections, audience and period of validity, ‘Disagree,’ or ‘Abstention,’ and the possibility of pro­
and methodology. viding comments in the case of disagree/abstention.
Recommendations were based on the level of best-
Twenty-four experts were present in the consensus
quality available evidence and good practice points meeting. The final literature search update was per­
(GPP). Expert consensus was provided wherever ade­ formed on 10th Μarch 2023, and did not result in
quate evidence is not available. The levels of evidence
changes in the recommendation boxes; new references
were graded according to the Oxford classification [1]. were added in the texts. The finalisation of the draft and
In brief, level 1 indicates the strongest evidence based on recommendations was conducted through emailing
a systematic review of randomized controlled trials or
among all co-authors in the first semester of 2023.
high-quality studies, level 2 is based on randomised or Compared with the guideline 2020 recommendations,
well-designed cohort or cross-sectional studies, level 3 in this update, the following recommendation boxes
is based on non-randomised adequately designed stu­
were kept the same: Box 1. Surgical excision of primary
dies, and levels 4 and 5 indicate the weakest evidence cutaneous squamous cell carcinoma (cSCC), Box 2.
based on a smaller number of patients or poor quality. Surgery and safety margins, Box 3. Wound closure, Box
The level may be graded down based on study quality,
4. Therapeutic lymph node dissection, Box 5. Elective
imprecision, indirectness, because of inconsistency be­ lymph node dissection, Box 6. Elective neck lymph node
tween studies, or because the absolute effect size is very dissection for mcSCC to the parotid, and Box 8. Pri­
small. The level may be graded up if there is a large or
mary Radiotherapy (RT). The following recommenda­
very large effect size. (detailed in Stratigos et al. Part tion boxes were updated: Box 7. Destructive modalities
1. 2023). for cSCC, Box 9. Postoperative RT, Box 12. Im­
The grades of recommendation were classified as
munotherapy for advanced cSCC, Box 13. EGFR in­
follows: hibitors, and Box 14. Follow-up. The following new
A: Strong recommendation. Syntax: ‘shall.’ boxes were added: Box 10. Adjuvant RT for resected
B: Recommendation. Syntax: ‘should.’
nodal metastatic cSCC, and Box 11. Adjuvant RT for
C: Weak recommendation. Syntax: ‘may/can.’ high-risk cSCC.
X: Should not be recommended. A summarising box of recommendations is provided
0: Recommendation pending. Currently, not avail­
at the end of the article containing the practice-oriented
able or sufficient evidence to make a recommendation in statements.
favour or against.
4 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252

1.2. Disclaimer shown a clear benefit for adjuvant RT in patients with

primary cSCCs with clear surgical margins.
Medicine is subject to a continuous development pro­ Systemic treatment options used for advanced cSCC
cess. This entails that all statements, especially with re­ include immunotherapy with programmed death re­
gard to diagnostic and therapeutic procedures, can ceptor-1 (PD-1) blocking antibodies, epidermal growth
only reflect scientific knowledge current at the time of factor receptor (EGFR) inhibitors, chemotherapy, and
printing of these guidelines. Utmost care was applied electrochemotherapy. Currently, the anti-PD-1 agent
with respect to stated therapeutic recommendations and cemiplimab is the only approved systemic treatment for
the selection as well as the dosage of drugs. cSCC in Europe. Cemiplimab is approved for the
Nevertheless, users are prompted to use package inserts treatment of patients with metastatic cSCC (mcSCC) or
and expert information by the manufacturers as backup locally advanced cSCC (lacSCC) who are not candidates
and, in case of doubt, consult a specialist. Pursuant to for curative surgery or radiotherapy,
the public interest, questionable discrepancies shall be A multidisciplinary approach is mandatory for all pa­
communicated to the Guideline Program in Oncology tients with advanced disease, considering the risks of toxi­
(GPO) editors. The user himself/herself remains re­ city, age, and frailty of patients, in addition to co-
sponsible for all diagnostic and therapeutic applications, morbidities, including immunosuppression [3]. The sys­
medications, and doses. Registered trademarks (protected tematic review by Leus et al. reported that the age of elderly
product names) are not specified in these guidelines. In the patients did not significantly affect surgery outcomes, in­
absence of respective indications, it may thus not be in­ cluding recurrence rate, complication rate, and disease-spe­
ferred that product names are unprotected. cific survival [4]. However, frailty may be a more relevant
This work is protected by copyright in all its parts. issue. Frail patients (Eastern Cooperative Oncology Group
Any utilisation outside the provision of the copyright performance status 2 or higher) have not been included in
act without the written permission by the GPO of the pivotal clinical trials for cSCC. Real-world studies report
European Association of Dermato-Oncology (EADO) some encouraging results for response and toxicity with anti-
is prohibited and punishable by law. No part of this PD-1 agents in frail patients with cSCC, although the
work may be reproduced in any way without written number of such included patients is currently small [5–7].
permission by the GPO. This applies in particular to All treatment considerations are based on the informed
duplications, translations, microfilming, and the sto­ consent of the patient (or an appointee having the legal
rage, application, and utilisation in electronic systems, authority to decide on the patient’s behalf in the case of a
intranets, and internet. patient lacking the mental capacity of informed consent,
according to national legal requirements) and on offering a
2. General considerations for the treatment of cSCC shared decision-making. The treating physician will inform
the patient about the first and other lines of treatment based
The primary treatment of cSCC is surgery, aiming at the on current best evidence and guidelines, explain the ex­
clinical and microscopic clearance of the tumour (R0 pected benefit and risks, and involve the preferences and
surgery). The preservation of function and cosmesis are priorities of the individual patient in the decision process.
additional objectives of treatment. Achieving clear sur­
gical margins is the most important treatment con­ 3. Surgery for common primary cSCC
sideration for patients with cSCCs amenable to surgery.
Radiotherapy may be considered as a primary treatment Surgical excision is considered the primary treatment of
in patients who are not candidates for surgery (e.g. lo­ primary cSCC, regardless of the age of the patient or the
cally infiltrating tumour, comorbidities, or declined anatomic location. Surgery provides a high rate of clin­
surgery) or in cases when curative surgery is not possible ical and microscopic complete resection (R0 surgery).
or could be disfiguring. The very low risk of radiation- Two different approaches may be offered: (1)
induced, in-field malignancy in the future, in patients Excision with standardised safety margins and post­
younger than 60 years old with cSCC, should be con­ operative margin assessment (where only part of the
sidered during the decision-making [2]. actual resection margin is being examined), or (2) mi­
Adjuvant therapy is defined as an additional treat­ crographically controlled surgery (3D) with a mapping
ment, either systemic or radiotherapy, given after com­ of the entire circumferential and deep tumour borders
plete resection at the primary surgical treatment (R0), followed by step-wise re-excisions in case of any residual
with the aim to reduce the risk of recurrence. While there tumour nests [8,9]. Frequently, a reconstructive proce­
are ongoing clinical trials investigating the potential dure (i.e. flap or graft closure) is necessary to repair the
benefit of adjuvant systemic therapy for cSCC, currently surgical defect resulting from tumour resection, but final
only adjuvant RT has been used in routine clinical reconstruction is strongly discouraged before histolo­
practice. The benefit of adjuvant RT to the nodal basin gical confirmation of clear margins [10]. The surgical
has been shown after lymph node dissection for cSCC management of tumours requiring extensive excisions
with nodal metastasis. However, current evidence has not should be performed by surgeons (dermato-surgeons,
 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252 5

Box 1 Surgical excision of primary cSCC.

Surgical treatment of primary cSCC Evidence-based recommendation

Grade of recommendation A Surgical excision with histological control shall be performed as standard treatment. The aim of cSCC
surgery shall be a complete excision (R0) with histological confirmation of peripheral and deep excision
margins.
Large tumours or tumours on the head and neck can undergo a punch or incisional biopsy for
histological confirmation and planning of a subsequent complete excision.
In cases of positive margins, a re-excision shall be done, for operable cases.
Level of evidence 2 Guideline adaptation [13,21].
Systematic review [31,46].
Retrospective study [39].
Strength of consensus: 100%.

Box 2 Surgery and safety margins.

Surgery and safety margins Evidence-based recommendation

Grade of recommendation B Low-risk cSCC should be excised with a clinical safety margin of 5 mm.
cSCC with high-risk factors should be excised with a clinical safety margin of 6–10 mm or by micrographically
controlled surgery.
Micrographically controlled surgery should be considered for cSCC in functional/cosmetical sensitive areas.
Level of evidence 2–3 Guideline adaptation [19–21,25,27].
Strength of consensus: 100%.

Box 3 Wound closure.

GPP As long as an R0 resection is not histologically confirmed, wound closure with local tissue movements (flaps) should be avoided.
Strength of consensus: 100%.

plastic surgeons or head, and neck surgeons) with ap­ high-risk criteria (listed in Guideline Part 1). There are no
propriate expertise in reconstructive procedures. randomised studies investigating optimal clinical safety
margins for excision. In clinically well-defined low-risk
3.1. Standard excision cSCCs with a diameter of less than 2 cm, a clinical safety
margin of 4 mm has achieved cure rates of 95–97% in
Surgical excision including all visible tumour borders prospective studies [16,17]. Nevertheless, diameter is only
together with a risk-adapted adjacent safety margin of an approximate reflection of the actual degree of tumour
clinically normal-appearing skin is the standard treat­ aggressiveness, and additional histological features may
ment of invasive cSCC [11]. Conventional excision increase the risk of margin involvement, even in smaller
should be followed by postoperative pathologic assess­ tumours [18]. Therefore, several national guidelines discuss
ment of resection margins to ensure an appropriate margins between 4 and 6 mm for tumours lacking high-
lateral and deep tumour-free margin and thus minimise risk features [2,13,19–22]. The European consensus group
the risk of local recurrence and metastases [2,12,13]. suggests a 5 mm clinical safety margin for low-risk lesions
Routinely, histological examination of the excised tu­ (Fig. 1). A recent prospective study reported a 98% com­
mour bed is performed in a cross-sectional fashion with plete excision in T1 tumours excised with a 5 mm margin
vertical sample cuts (bread-loaf sections for 2D his­ versus 91% of T2 tumours and 81% of T3 tumours excised
tology) obtained from formalin-fixed, paraffin-em­ with 1 cm. Most of the residual tumour involved the deep
bedded tissue [9,14]. margin [23]. In the event, that a cSCC thought to be a low
Clinical safety excision margins should be adapted to risk at biopsy is proven to be a high risk after excision with
the likelihood of subclinical extensions and recurrence [15], a 5 mm clinical safety margins, a re-excision with a his­
as defined by high-risk factors including clinical (tumour tological clear margin can be discussed.
diameter > 2 cm, high-risk sites), histological (thickness > For high-risk cSCC, however, even though wider
6 mm or invasion beyond subcutaneous fat, perineural margins are recommended, there is currently no unified
invasion, poor differentiation, desmoplasia), and patient- recommendation on appropriate safety margins [24].
related criteria (immunosuppression) (EADO list of Some recent guidelines discuss the need for complete
6 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252

excision without further specifying margins or em­ 3.2. Micrographically controlled surgery
phasise the value of micrographically controlled sur­
gery in high-risk and very high-risk cSCC, primarily Micrographically controlled surgery is used as a collective
due to the wide variability of characteristics that may term for a range of surgical techniques used to remove
define cSCC at higher risk [10,13,14]. According to an skin cancer with complete margin control. These stepwise
early work from Brodland et al., for larger cSCCs procedures allow for peritumoural examination that is
(> 2 cm in maximum clinical diameter) and/or other repeated until all circumferential and deep borders are
high-risk factors, an excision margin of at least 6 mm is completely free of tumour. Micrographically controlled
required [16]. The British guideline recommends ≥6 mm surgery thus provides complete margin assessment, en­
for high-risk, and ≥10 mm for very high-risk cSCC [2]. ables histological clearance prior to reconstruction, and
Additional recommendations from reviews or guide­ minimises the removal of uninvolved tissue [31]. Two
lines also vary from a lower limit of six up to ≥10 mm, techniques are mainly being used in Europe with diverse
or favour micrographically controlled excisions as modification of sectioning the tissue specimen: Mohs mi­
a first-line treatment instead [20,22,25–27]. As the in­ crographic surgery (MMS) and 3D histology [32], the first
dependent prognostic effect of high-risk factors has not one making use of intra-operative frozen sections whereas
been consistently reported, a specific recommendation the second one uses paraffin sections [33] ([Link]
on the clinical safety margins cannot be given but [Link]/fileadmin/user_upload/ESMS_Position_Paper_-_
should fall within the 6–10 mm range and be based on [Link]). The NCCN Guidelines on cSCC use the de­
individual risk assessment and tumour- and patient- scriptive term ‘Peripheral and deep en face margin as­
related characteristics (Fig. 1). In addition to the sessment (PDEMA)’, instead of the previous term
European consensus group, the Japanese Dermatology ‘complete circumferential peripheral and deep margin as­
Society suggests 6–10 mm safety margins for cSCC sessment (CCPDMA),’ referring to the techniques, in
with high-risk factors [21,22]. A retrospective study which the entire marginal surface of the surgical specimen
from Japan has challenged the need for wider excision (including the complete deep and peripheral margin) is
margins in high-risk and very-high-risk (according to microscopically visualised and histopathologically ana­
National Comprehensive Cancer Network [NCCN] lysed for the presence of SCC [13]. Among the available
guidelines) cSCC patients. They compared two cohorts techniques and modifications of micrographically con­
excised either with safety margins adherent to national trolled surgery achieving this purpose of en face margin
guidelines (6–10 mm) or with narrower margins assessment are MMS with frozen sectioning, or the Tü­
(≤5 mm). Though there was a significantly higher in­ bingen Muffin (Supplementary Fig. 1) and Tübingen
complete excision rate in the narrow-margin-group of Torte techniques, both employing formalin fixation and
very-high-risk tumours, the authors did not find sig­ paraffin embedding and complete margin assessment
nificant differences between both groups with regard to [13,34] ([Link]
a cumulative incidence of local relapse, cSCC relapse MS_Position_Paper_-_WEB.pdf). Furthermore, the
(local, regional nodal, or distant relapse), or cSCC NCCN guidelines include a checklist to apply before
death [28]. naming a technique PDEMA as many other surgical
In patients with skin areas covered by a cluster of mul­ techniques exist such as square technique, perimeter
tiple invasive cSCCs (e.g. on the dorsal hands or scalp), en technique, moat technique, and quadrant technique where
bloc excision of the involved field with subsequent skin the deep margin is examined in vertical sections and
grafting can be offered as an effective treatment. therefore a complete visualisation of the deep margin is
The depth of excision should include the sub­ not given [13]. An advantage of MMS is that the tumour
cutaneous tissue (together with the underlying galea- can be removed and on the same day a reconstruction can
aponeurosis in scalp locations) while sparing the peri­ be performed shortly after. There have been attempts to
chondrium or periosteum, provided these structures are replace the traditional MMS frozen tissue with the use of
not affected by the tumour [19]. fresh-tissue sections examined intra-operatively by ex-vivo
In the case of positive margins, a re-excision shall be confocal microscopy [35], but in cSCC, this approach has
done for operable cases. Wider excision should be yet failed at reliably detecting small areas of residual tu­
considered when margins appear more limited than the mour or more specific morphological features such as
recommended safety margins, as described in the pa­ perineural growth.
thology report, after considering the tissue shrinkage There is no randomised trial that compares micro­
during the process (Fig. 1). graphically controlled surgery techniques with conventional
Instead of extended standard margins, micro­ surgical excision for cSCC [11,31]. Micrographically con­
graphically controlled surgery should be considered in trolled surgery provides the highest rate of R0 resection,
selected cases of high-risk cSCC, though evidence of the above 90%, and lower recurrence rates (0–4%) compared
superiority of the method over standard excisions is to conventional surgery (recurrence rates: 3.1–8.0%)
based only on retrospective studies [29,30]. [11,29,31,36–43].
 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252 7

The systematic review and meta-analysis of Fraga 4. Surgery for regional nodal disease
et al. compared recurrence for complete margin as­
sessment versus excision with sectional assessment in The evidence about the management of regional nodal
high-risk keratinocyte carcinomas. They reported sig­ disease in patients with cSCC is limited and largely
nificantly lower locoregional recurrences with complete based on studies performed in head and neck mucosal
margin assessment versus sectional assessment for all SCC [47,48]. It is likely that patients with nodal me­
keratinocyte carcinomas (3.9% versus 13.5%, p = 0.001) tastases from cSCC should be managed surgically in a
and for cSCC with PNI (9.8% versus 32%, p < 0.001) similar way to patients with other skin cancers (mela­
[44]. The value of MMS has been documented, espe­ noma or Merkel cell carcinoma). For all tumours not
cially for head and neck tumours [11,36–38]. The value amenable to surgery (due to patient-related factors or
of MMS in the prevention of local recurrence has been when the intention of a R0-resectability cannot be
reported in retrospective studies. In one study, in­ achieved), radiotherapy should be considered based on a
cluding 647 high-risk cSCC there were 19 local re­ multidisciplinary tumour board decision. Appropriate
currences (LR) (2.9%), 31 nodal metastases (4.8%), staging to determine the extent of disease is detailed in
seven distant metastases (1.1%), and seven disease- Stratigos et al. Part 1. 2023.
specific deaths (DSD) (1.1%) [39]. The other retro­ Therapeutic regional lymph node dissection for lymph
spective study including 579 patients with 672 cSCCs of nodes clinically detected or following imaging is the pre­
the head and neck (380 treated with MMS and 292 with ferred surgical treatment [13,27,49–58]. A radical lymph
standard excision) concluded that MMS might be su­ node dissection of the affected areas is still considered the
perior to standard excision for cSCCs of the head and standard of care for patients with resectable nodal disease.
neck because of a lower recurrence rate after adjust­ However, in view of the lack of overall survival benefits
ment for tumour size and deep tumour invasion (3% from radical dissections, the extent of surgical resection,
versus 8%) [29]. that is, the levels of axillary nodes, whether to remove deep
When modelling the expenses of MMS under theo­ inguinal nodes, should always be determined for each pa­
retical assumptions based on the data from previous tient by the interdisciplinary tumour board. Neck dissection
studies on intermediate risk cSCC, MMS was more cost- in addition to superficial parotidectomy should be per­
effective than wide local excision in an outpatient setting formed if the parotid gland is affected, since a lower disease-
[45]. The higher complexity of this multistep procedure specific survival was observed with radiation therapy alone
usually limits its use to patients with high-risk tumours, [59]. It is unclear whether a more selective procedure will
in whom micrographically controlled surgery provides affect the disease-free survival and the overall survival.
the best guarantee for complete tumour resection with Accordingly, over the last decade, a trend towards the
optimal anatomic, aesthetic, and functional preserva­ consideration and offer of less extensive and more selective
tion. In conclusion, the various modifications of mi­ lymph node dissections has developed, particularly with
crographically controlled surgery are tissue conservative head-and-neck cSCC patients, where this approach has
and effective treatments in cases of high-risk cSCC, shown regional control and survival rates of 85–100%, si­
particularly in the head and neck area. milar to those reported for conventional radical neck

Box 4 Therapeutic lymph node dissection.

Therapeutic lymph node dissection Evidence-based recommendation

Grade of recommendation: B A regional therapeutic lymph node dissection should be performed in patients with lymph node
metastasis detected clinically or by imaging tests and confirmed with cytology or biopsy.
The extent of surgical resection is determined by the surgeon in collaboration with the multidisciplinary
tumour board.
Level of evidence: 3 Review [49,50].
Prospective study [51].
Retrospective study [52–56,58].
Guidelines [13,27,57].
Strength of consensus: 100%.

Box 5 Elective lymph node dissection for N0 cSCC.

Elective lymph node dissection for cSCC Evidence-based recommendation

Grade of recommendation: X Elective lymph node dissection shall not be performed for N0 cSCC.
Level of evidence: 4 Evidence for elective lymph node dissection for N0 cSCC is lacking [49].
Strength of consensus: 100%.
8 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252

Box 6 Elective neck lymph node dissection for mcSCC to the parotid.

Elective neck lymph node dissection for metastatic cSCC to Evidence-based recommendation
the parotid

Grade of recommendation: C Elective neck dissection may be discussed and offered for metastatic cSCC
within the parotid.
Level of evidence: 3 Meta-analysis [63].
Strength of consensus: 100%.

dissections [56,60,61]. Thus, the extent of lymph node dis­ 5.2. Other destructive treatments: Cryosurgery,
sections should be discussed in the context of the inter­ lasers, PDT
disciplinary tumour board and after a thorough assessment
of tumour-related (aggressiveness, involved regional basin, Cryosurgery, superficial skin ablation (laser, dermab­
tumour burden, etc.), surgical (potential complications, rasion), or photodynamic therapy share the lack of
morbidity, etc.), and patient-related features (overall con­ histological control and thus may increase the risk of
dition, performance status, preferences, expectations, etc.). recurrences, eventually leading to surgery in even poorer
Also, the current approach to lymph node disease, conditions. NCCN guidelines on cSCC list laser abla­
particularly for those patients with large-burden nodal tion among therapeutic options in field cancerization or
disease, will be revisited if/when neoadjuvant therapy be­ actinic cheilitis [13], but there is no evidence to consider
comes available. A recently published phase II clinical trial the use of lasers in invasive cSCC [11,66]. PDT is only
of neoadjuvant cemiplimab reporting pathological com­ approved in Bowen’s disease (in situ cSCC), but there is
plete response in 50% of the patients favours this future inadequate evidence regarding its efficacy for invasive
approach [62] (see Section 8. Neoadjuvant therapy). cSCC. Also, when used in field cancerization, the effect
of PDT to prevent the development of new SCC remains
5. Treatment alternatives limited [67,68]. A systematic review and pooled analysis
of observational studies reported low recurrence rates
5.1. Curettage & electrodessication (C&E) after cryotherapy, but most cSCC included were small
and low-risk tumours, and the quality of evidence was
There are no prospective studies comparing curettage low [11]. AAD guidelines state that cryosurgery may be
alone or C&E with other treatments. In a retrospective considered for low-risk cSCC when more effective
series of 89 mostly well differentiated and smaller cSCC therapies are contraindicated or impractical, which is
(mean pretreatment size 0.9 cm) removed by curettage rather uncommon [66]. Nevertheless, in selected cases of
alone, Yakish et al. reported an overall cure rate of 97% low-risk cSCC, particularly in patients with extensive
after a median follow-up of 6 years [64]. A systemic review field cancerization, cryotherapy can be offered [13,69].
and pooled analysis of observational studies on combined Surgery should be discussed and considered with
C&E reported low recurrence rates for small cSCC preference to any destructive and ‘blind’ options.
(< 2 cm) [11], which was confirmed by a recent meta-
analysis for in situ and invasive cSCC, studied together
[65]. Updated NCCN guidelines 2023 and an expert con­ 5.3. Intralesional cytostatic drugs
sensus in the American Academy of Dermatology (AAD)
guidelines state that C&E may be considered for small, Minimal invasive intralesional treatments could be al­
low-risk primary cSCC (based on NCCN risk stratifica­ ternatives in select patients for whom surgical excision is
tion) [10,13]. C&E (two cycles) in experienced hands can not acceptable and are particularly among non-surgical
be performed in small, low-risk tumours, and in selected options suggested in those with keratoacanthomas
cases (patients with multiple cSCCs), but surgery is always (KA). In cSCC, the injection of 5-fluorouracil has been
to be preferred to this blind method. recently analysed in a retrospective cohort with a total

Box 7 Destructive modalities for cSCC.

Destructive modalities Consensus-based recommendation

GPP Destructive modalities such as ED and C, cryotherapy, PDT, and lasers should not be performed in the treatment of
primary invasive cSCC. Exceptions can be considered in small-sized and/or multiple cSCCs in low-risk areas where
surgery and/or RT are not possible or have unacceptable consequences.
Strength of consensus: 100%.
 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252 9

of 172 lesions (majority < 2 cm in diameter, pre­ beams or photons. Treatment can be delivered to a
dominantly located on legs, including seven KA). small superficial area (e.g. nasal ala) or a large complex
Treatment was well tolerated and followed by clinical volume (e.g. whole scalp or skull base).
resolution in 92% of cases [70]. In KA, when a sugges­ The total prescribed dose and fractionation should
tive history of a rapid development together with clinical reflect the differences in radiobiological effectiveness
and histological features are typical, intralesional in­ between different radiation modalities. Doses of
jection of several cytostatic drugs (methotrexate, 5- 60–64 Gy in fractions of 2 Gy for tumours of < 2 cm (or
fluorouracil, or bleomycin) may be considered to reduce other schedules with equivalent radiobiological dose)
scarring in a potentially self-healing lesion. However, an and 60–70 Gy in fractions of 2 Gy for tumours of
advantageous benefit-risk ratio has not yet been de­ > 2 cm (or other schedules with equivalent radio­
monstrated, particularly when compared with surgery biological dose) are recommended. Hypo-fractionated
[71–73]. If complete regression is not achieved, the lesion RT (larger dose per fraction) has been shown to have
should be surgically removed to exclude the risk that equally high efficacy and could result in better patients’
this lesion is a more aggressive SCC. compliance (fewer fractions) [74]. Interventional radio­
therapy could also be proposed based on the tumour
size and location as an alternative to EBRT.
6. Radiotherapy Radiotherapy is an overall safe procedure, although it
may be associated with complications such as an acute
6.1. Primary definitive radiotherapy radiation-induced dermatitis and chronic onset of de­
pigmentation and telangiectasias. The latter will become
Definitive primary radiotherapy represents a valid al­ more visible over the years, and this must be considered
ternative and curative treatment strategy to surgery for when offering treatment for younger patients. Higher
small cSCCs. RT should be considered as the primary doses per fraction lead to higher rates of late toxicity [75].
treatment option in patients who are not candidates for Therefore, hypofractionation schedules should be pro­
surgery (e.g. locally infiltrating cSCC not amenable to posed for the elderly, especially frail patients, or when
surgery, presence of comorbidities, or when patients the long-term cosmetic outcome is of lesser importance.
decline surgery) or in cases when curative surgery is not Prescribed doses must encompass all visible tumour
possible or could be disfiguring or burdened by the poor plus an appropriate variable margin (clinical target vo­
functional outcome, especially cSCCs located on the lume), sparing as much as possible of the surrounding
face (i.e. eyelid, nose, lip) or large lesions on the ear, healthy structures [76–78]. Irrespective of treatment in­
forehead, or scalp (Fig. 1). tent (definitive, adjuvant, palliative), dosimetry and
Prospective randomised trials comparing the effec­ technical considerations should be surveyed by a certi­
tiveness of primary radiotherapy in terms of local tu­ fied radiation oncologist.
mour control and patient survival compared to other RT may be combined with systemic therapies in­
local therapy modalities are not available. A meta- cluding immunotherapy, chemotherapy, or targeted
analysis (2013) of 14 observational studies of radio­ therapies (i.e. cetuximab) in more advanced cases.
therapy for 1018 primary cSCCs reported a pooled
average local recurrence rate of 6.4% [11].
Modern radiotherapy represents a versatile treatment 6.2. Postoperative RT
modality and depending on tumour and/or patient fac­
tors can be delivered as an external beam technique or 6.2.1. Definitive postoperative radiotherapy
via brachytherapy (Interventional Radiotherapy, BT, Definitive postoperative RT should be considered after
IRT). External beam RT (EBRT) may involve electron surgical excision for cSCC with positive margins

Box 8 Primary RT.

Definitive primary RT Evidence-based recommendation

Grade of recommendation B Primary radiotherapy should be considered as an alternative to surgery for inoperable or difficult-to-operate
tumours or in the absence of consent to surgical excision.
Level of evidence 3 Systematic review/meta-analysis, high risk of bias [11].
Retrospective studies in small numbers and heterogeneous group of patients [79,80].
Strength of consensus: 100%.

RT, radiotherapy.
10 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252

Box 9 Postoperative RT.

Postoperative RT Evidence-based recommendation

Grade of recommendation B Postoperative radiotherapy should be considered after surgical excision for cSCC with positive margins and
for which re-excision is not possible.
Level of evidence 3 Meta-analysis (20 observational studies and one randomized phase III study) [48].
Randomized phase III study [96].
Retrospective studies [47,81,97,98].
Guidelines [95].
Strength of consensus: 100%.

(residual microscopic [R1] or macroscopic [R2] tumour) of the head and neck. However, there is a lack of
where re-excision is not possible [13,27,81,82]. The re­ significant evidence, including randomised controlled
commended dose for postoperative RT is 60–66 Gy in trial data, showing a clear benefit of adjuvant RT in
30–33 fractions, five fractions per week [27,81–83], but this setting [46,79,81,84–88]. An important limitation
in the case of R2, specific considerations should be made of most studies on the use of adjuvant RT for primary
according to the size of residual disease. common cSCC is the fact that they do not specify the
The majority of studies defining risk factors for local results of histological margin assessment or include
recurrence are restricted to the head and neck area. An patients treated with RT for cSCC with positive
international consensus guideline by the Head and Neck margins as well as those with negative margins. Re­
Cancer International Group (HNCIG) for the delivery cent studies have shown no benefit for adjuvant RT
of postoperative RT in the head and neck region was focusing on cSCC with clear surgical margins [89–92].
published in 2020 [78]. The guideline from HNCIG also The meta-analysis of Kim et al. in high-risk non-me­
includes a detailed description of the recommended tastatic cSCC (any high-risk factor present) treated
radiotherapy techniques to be used. with margin-negative resection (29 retrospective, two
prospective, two case series), reported no statistically
6.2.2. Adjuvant radiotherapy significant differences in poor outcomes between sur­
Adjuvant RT refers to RT performed after complete gery alone and surgery with adjuvant RT [90]. On the
surgical resection of the tumour (R0). Adjuvant RT is other hand, the meta-analysis of Zhang et al. reported
offered as part of clinical practice in many medical lower recurrence, longer disease-free survival, and
centres for patients with high-risk cSCC, particularly longer overall survival with adjuvant radiotherapy,
for tumours with PNI. Current practice is influenced but included primary as well as metastatic cSCC, and
by the standard use of adjuvant RT for mucosal SCC the benefit of adjuvant RT may have concerned nodal

Box 10 Adjuvant RT for resected nodal metastatic cSCC.

Adjuvant RT for resected Evidence-based recommendation

nodal cSCC

Grade of recommendation B Adjuvant radiotherapy following therapeutic lymphadenectomy should be considered in cSCC of the head
and neck with regional nodal metastases and extracapsular extension.
Level of evidence 3 Meta-analysis (20 observational studies and 1 randomized phase III study) [48].
Randomized phase III study [96].
Retrospective studies [47,81,97].
Guideline [95].
Strength of consensus: 100%.

Box 11 Adjuvant RT for high-risk cSCC.

Adjuvant RT Evidence-based recommendation

Grade of recommendation C Adjuvant radiotherapy may not be offered as standard of care for cSCC with clear surgical margins, as a clear
benefit has not been shown.
Level of evidence 3 Retrospective studies [89,91,92].
Meta-analysis [90].
Strength of consensus: 100%.
Grade of recommendation C Adjuvant radiotherapy may be discussed for cSCC with multiple high-risk factors (BWH T2b/T3) and with
clear surgical margins.
Level of evidence: 4 Retrospective study [94].
Strength of consensus: 97%.
 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252 11

metastatic cSCC [93]. Adjuvant RT was associated non-randomised study in 79 patients with resectable
with a lower risk for locoregional recurrence com­ stage II, III, or IV (M0) cSCC evaluated neoadjuvant
pared to surgery alone, for cSCC with multiple high- cemiplimab 350 mg every 3 weeks for up to four doses,
risk factors (at least 2 BWH risk factors) in the study before undergoing surgery with curative intent. A pa­
of Ruiz et al. There was no significant effect on the thological complete response was observed in 40 pa­
risk for disease-specific death [94]. tients (51%), and a pathological major response in 10
Regarding nodal metastatic cSCC, adjuvant RT has patients (13%). The second part of this study allowed for
been recommended for cSCC of the head and neck optional adjuvant cemiplimab therapy, adjuvant RT, or
following lymph node dissection, although it may not be observation only and will be reported in the future [62].
necessary in immunocompetent patients with a single, A recommendation cannot yet be given on the use of
small cervical lymph node metastasis (< 3 cm) without neoadjuvant therapy due to the relatively small sample
extracapsular extension. Adjuvant RT can be con­ size and immature follow-up to date. The NCCN ver­
sidered for surgically treated cSCC of the trunk with sion 1.2023 guidelines recommended that neoadjuvant
nodal metastasis following lymph node dissection, al­ cemiplimab may be considered in patients with nodal
though the evidence is less robust compared to cSCC of metastasis who are considered borderline resectable,
the head and neck [13,48,95]. unresectable, or for whom surgery may carry a high
morbidity [13]. Clinical trials in the neoadjuvant setting
7. Adjuvant systemic therapy are ongoing.

There are no solid data to support the use of adjuvant 9. Treatment for in-transit metastases
systemic treatment in localised cSCC after R0 resection
(clear surgical margins) [96,99–103]. There was no im­ Satellite or in-transit metastases should be removed
provement in time to recurrence or time to second pri­ surgically if the number, size, and location allow
mary tumours with adjuvant 13-cis-retinoic acid plus complete removal of the metastatic sites. According to
interferon alpha [101]. Adjuvant chemotherapy (oral a case series, adjuvant radiation therapy can be helpful
capecitabine and other systemic cytotoxic drugs) or in such cases [110]. For multiple unresectable metas­
targeted therapies (EGFR inhibitors) should not be re­ tases on the limbs, amputation used to be a common
commended, since robust evidence about efficacy based option; however, currently it is no longer performed as
on survival data is lacking [102]. A small retrospective it has no proven impact on the prognosis and several
study in patients with resected high-risk cSCC (majority local and systemic alternatives are available to prevent
with clear margins) investigated RT combined with ce­ mutilation [110]. Local options include radiotherapy,
tuximab (n = 29) or RT alone (n = 39). There were better intralesional chemotherapy (5-fluorouracil, bleomycin,
progression-free survival (PFS) rates for the combina­ or methotrexate), intralesional recombinant interferon
tion therapy than with RT alone (2-year: 72% versus alpha, electrochemotherapy, or isolated limb perfusion
53%, 5-year: 66% versus 29%, respectively) [103]. In a [110–114]. Systemic options include oral retinoids,
recent prospective phase II trial of adjuvant radio­ chemotherapy (platin-based regimens), EGFR in­
therapy with concomitant cetuximab for high-risk cSCC hibitors, and anti-PD1 immunotherapy [110,111]. The
(T3–4 or ≥N1) of the head and neck after definitive re­ only systemic drug approved in this setting is the
section (R0 or R1), the 2-year loco-regional control rate anti-PD1 agent cemiplimab [115] (Fig. 1). Reduction
was 91.1% and the disease-free survival was 70.8%. or withdrawal of immunosuppressive drugs should
These results compared favourably to historical retro­ be considered in iatrogenic immunosuppressed
spective data of adjuvant radiation alone, holding pro­ patients [110].
mise for the treatment of patients at high risk for disease
recurrence [104]. 10. Systemic treatments for advanced cSCC
Currently, randomised clinical trials in the adjuvant
setting with radiotherapy, cemiplimab, and pem­ 10.1. Immunotherapy with checkpoint inhibitors
brolizumab are ongoing.
cSCCs are known to be UV-radiation-driven skin can­
8. Neoadjuvant therapy cers with the highest rate of somatic tumour mutations.
The tumour mutational burden (TMB) refers to the
Neoadjuvant therapy aims to reduce the size of a tu­ number of genetic changes in a cancer cell [116]. The
mour prior to surgery, so that there is a smaller surgical immune system can identify cancer cells and activate an
defect and easier reconstruction. There are a limited immune response by detecting altered cellular proteins –
number of small studies of neoadjuvant EGFRi therapy so called neoantigens – based on these mutations.
[105–108]. A pilot phase 2 study of neoadjuvant cemi­ Therefore, cSCC is of great interest for treatment with
plimab in 20 patients reported 70% complete or major immune checkpoint inhibitors. The TMB rate in cancer
pathological responses [109]. A phase 2, multicentre, has been correlated to the response rate of PD1
12 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252

Box 12 Immunotherapy for advanced cSCC.

Immunotherapy for locally advanced or Evidence-based recommendation

metastatic cSCC

Grade of recommendation B Patients with metastatic cSCC or locally advanced cSCC, who are not candidates for curative
surgery or curative radiation, should receive first-line treatment with a PD-1 antibody*.
Level of evidence 2 Phase 1 and 2 study of cemiplimab. [115,119–121].
Phase 1 and 2 of pembrolizumab. [124,125,127,130].
Strength of consensus: 100%.
*
In Europe, cemiplimab is currently the only approved medication, while pembrolizumab and nivolumab are investigated in clinical studies.

antibody treatment [117]. A relatively high expression of Food and Drugs Administration (FDA) in September
PD-ligand 1 (PD-L1) with immunohistochemistry 2018 and by the European Medicines Agency (EMA) in
staining has been reported for cSCC [118]. This high July 2019 (Fig. 1). Later, the EMA requested a con­
PD-L1 expression may also correlate to the tumour re­ firmatory study for the approved dose of 350 mg cemi­
sponse of PD1-antibodies. plimab. The latest results of this trial (EMPOWER-
A pivotal clinical trial for cSCC with cemiplimab, a CSCC-1; group 6) have been presented at the ESMO
PD-1 antibody, has been reported by Migden and co- conference in September 2022 as well [123]. A total of 167
workers [115]. In this phase 2 non-randomised clinical patients with metastatic or locally advanced disease have
trial (‘EMPOWER-CSCC-1’), 59 adult cSCC patients been treated. 59.9% were metastatic, whereas 40.4% had
with metastases and 78 patients with locally advanced a locally advanced disease. The median duration of ex­
disease who were not candidates for curative surgery or posure to cemiplimab was 35.7 weeks. After a relatively
irradiation were treated with 3 mg/kg body weight cemi­ short follow-up of only 8.7 months, the following results
plimab every 2 weeks for up to 2 years. Another 56 adult have been released. Overall response rate: 45.1% in­
patients with metastatic cSCC received cemiplimab with cluding 5.5% complete responses. The median progres­
a flat dose of 350 mg every 3 weeks intravenously for up sion-free survival was 14.7 months, whereas the duration
to 1 year. 33.7% of the whole study population had re­ of response and overall survival have not reached the
ceived prior systemic therapy. The end-point of the median yet. 13.9% of the patients discontinued the
clinical trial was the response rate assessed by an in­ treatment due to adverse events, and none of the ob­
dependent review committee per Response Evaluation served deaths were considered to be related to cemi­
Criteria in Solid Tumors (RECIST) 1.1 (for scans) and plimab by the investigators. The most frequent adverse
modified World Health Organisation (WHO) criteria (for events were fatigue (26.1%), diarrhoea (21.2%), and
photos). This clinical trial was presented at many meet­ pruritus (21.2%) [123].
ings and received several updates [119–121]. (Table 1). In Another PD-1 antibody, pembrolizumab, has been in­
the final analyses from September 2022 (European So­ vestigated in a phase 2 trial (KEYNOTE-629) [124].
ciety of Medical Oncology (ESMO) 2022) [122], with a However, in this clinical trial, the vast majority of patients
median follow-up of 15.3 months, the following results have been pretreated with chemotherapy and only a small
were obtained for the three groups of the EMPOWER- subgroup was treatment-naïve. One hundred and five lo­
cSCC-1 trial: Response rate (overall response rate [ORR], cally advanced and metastatic cSCC patients have been
complete response [CR], partial response [PR]): group 1 included. The objective response rate was 34.3% including
(50.8%, 20.3%, 30.5%), group 2 (44.9%, 12.8%, 32.1%), 3.8% complete responses. The median progression-free
group 3 (46.4%, 19.6%, 26.8%). Summarising the results survival was 6.9 months, the median overall survival has
of the three groups (n = 193), the response rate is 47.2% not been reached. At 12 months, 60.3% of the patients
including 17.1% complete responses and 30.1% partial were still alive. The tolerability was very similar to the
responses. The median duration of response is 41.3 phase 2 trial on cemiplimab. The treatment discontinua­
months, the progression-free survival is 22.1 months, and tion rate accounted for 12.1% [124]. A subsequent update
the median of the overall survival has not been reached at on KEYNOTE-629 [125] confirmed the antitumour ac­
the data cut-off. A total of 10.4% of patients needed to tivity of pembrolizumab in both locally advanced and
discontinue the treatment due to adverse events. Most of metastatic cSCC patients and demonstrated no un­
the adverse events were fatigue, diarrhoea, nausea, and expected new safety signals. However, pembrolizumab has
pruritus. There were no new treatment-related adverse not been approved by EMA in Europe, whereas it is
events leading to death [122]. FDA-approved since June 2020 for locally advanced and
Cemiplimab was approved for metastatic and locally metastatic cSCC patients [125]. Thus, cemiplimab remains
advanced cSCC patients, who are not candidates for the only approved medication in Europe at this point of
curative surgery or curative radiation therapy, by the time (January 2023).
 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252 13

In a systematic review, Keeping et al. performed an small molecule tyrosine kinase inhibitors (TKI), including
indirect comparison on the efficacy of cemiplimab versus erlotinib, gefitinib, and lapatinib.
other systemic treatments for advanced cSCC in 11 studies Cetuximab is a chimeric monoclonal antibody that
(phase 2 study of cemiplimab NCT02760498 (n = 193), inhibits EGFR by targeting the extracellular domain of
seven studies on EGFRi, two trials on pembrolizumab, the EGFR and by blocking the intracellular signalling
one trial on platinum chemotherapy [126]). In indirect via the RAS/MAPK kinase pathway. Cetuximab is the
comparison, cemiplimab versus EGFRi was associated EGFRi mainly investigated for advanced cSCC, while
with benefits in overall survival (OS) (hazard ratio (HR) panitumumab has been assessed in a small number of
range: 0.07–0.47) and PFS (HR range: 0.30–0.67 in var­ patients [133–135]. Panitumumab alone or in associa­
ious studies). Cemiplimab versus pembrolizumab showed tion with radiotherapy in 25 patients, demonstrated a
more benefit in OS (HR range: 0.17–0.52), and in PFS best overall response of 52% in unresectable cSCC, al­
(HR range: 0.49–0.55) with data from KEYNOTE-629 though the prognosis was overall very poor with a
[124], but PFS was not different versus pembrolizumab in median PFS of 6.9 months and a median OS of 10.5
the study of Maubec et al. [127]. Cemiplimab was more months [135]. The evidence for erlotinib, gefitinib, and
efficacious in OS versus platinum-based chemotherapy lapatinib is very limited [107,136,137].
(HR: 0.19, 95% confidence interval (CI): 0.10–0.39), while
not statistically different in PFS (HR: 0.66, 95% CI:
0.38–1.16) [128]. 10.2.1. Cetuximab, chemotherapy, or combination of
Another systematic review and non-randomised treatments
comparison analysis by Petzold et al. included 22 studies Cetuximab is approved for the treatment of locally ad­
investigating chemotherapy, targeted therapy to EGF, vanced or metastatic head and neck SCC, in combina­
immune checkpoint blockade (ICB) (cemiplimab, pem­ tion with RT for locally advanced disease and with
brolizumab, nivolumab), and combination therapies. platinum-based chemotherapy for recurrent and/or
They reported that ICB showed the highest median PFS metastatic disease. Cetuximab has been used off-label,
(9.9 months [8.1–19.9]) and median OS (not reached, either alone [138–141], or combined with RT or cis­
[95% CI: 31.5 months-not reached]), compared to che­ platin, for advanced cSCC in small trials or case series
motherapy (PFS: 3 months, OS: 12.6 months), targeted [142–148]. Cetuximab is considered a radiosensitizer,
therapy to EGF (PFS: 4.9 months, OS: 12.7 months), with a synergistic effect in combination with RT
and combination therapies without ICB (PFS: 9.1 [99,149]. A prospective study of 20 patients with lacSCC
months, OS: 18.1 months). The survival benchmark compared cetuximab alone versus cetuximab combined
with ICB after 26 months for metastatic cSCC was with cisplatin or RT (60–70 Gy). Combination therapy
70.8% (95% CI: 61.5–81.5) versus 17.1% (9.5–30.8) for had higher response rates versus cetuximab alone (dis­
chemotherapy and 37.9% (29.5–48.8) for the combina­ ease control rate: 92% versus 50% and response rates
tion group [129]. 53% versus 33%, respectively). However, there was
a short duration of response (OS 11.1 months, PFS 5.7
months) [150]. Prospective studies of treatment with
10.2. EGFR inhibitors EGFRi are detailed in Table 2. EGFR inhibitors are
generally well tolerated compared to standard cytotoxic
Overexpression of EGFR has been demonstrated in ad­ agents. Most adverse events are cutaneous, dose-de­
vanced cSCC [131]. In addition, genetic activation of pendent and affect aesthetically sensitive areas with a
EGFR by mutations was reported in a small subset of great impact on patient’s quality of life. They include a
cSCC (2.5%) [132]. Available targeted EGFR inhibitors papulopustular/acneiform rash, which usually appears
(EGFRi) include antibody-based inhibitors of the extra­ within the first 1–2 weeks of initiating treatment,
cellular domain of EGFR (cetuximab, panitumumab) and xerosis, pruritus, and hand/nail toxicity [138].

Box 13 EGFR inhibitors.

Evidence-based recommendation

Grade of recommendation: C Cetuximab may be used for patients with locally advanced and metastatic cSCC, who have failed to respond
or are intolerant to immunotherapy. Cetuximab combined with RT is favoured over cetuximab monotherapy.
Level of evidence: 3 Small number of patients in prospective studies [141,150].
A small number of patients with metastatic cSCC treated [138,142,143,150,157,158].
Only two prospective non-randomized study in a small number of patients [147,150].
Small number of patients from retrospective studies [143,144,148,158].
Strength of consensus: 100%.
14 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252

Cetuximab may be used in patients with contra­ seem more effective than monochemotherapy but result in
indications or non-responders to anti-PD-1 (cemi­ more side-effects and poor tolerance, particularly in the
plimab), favouring its combination with chemotherapy elderly population that characterises advanced cSCC. In
or RT (Fig. 1). Ongoing clinical trials are investigating general, responses are mostly short-lived, are followed by
the combination of EGFRi and immunotherapy or rapid recurrence, and do not lead to a curative effect. In
different EGFRi to re-stimulate the antitumour immune general, monochemotherapy should be preferred while
response in patients with cSCC refractory to PD-1 in­ polychemotherapy should be reserved for cases requiring
hibitor therapy [151]. more aggressive management. A German retrospective
Currently, there are no systemic chemotherapies ap­ study investigated chemotherapy and EGFRi for ad­
proved for advanced cSCC patients. Data on chemother­ vanced cSCC in 59 patients with metastatic or locally
apeutic agents (e.g. platinum agents, 5-fluorouracil, advanced cSCC. During median follow-up of 52 weeks,
bleomycin, methotrexate), used either as monotherapy the overall response rate was 14.3%, and the disease con­
or polychemotherapy for the treatment of advanced trol rate was 53.6%. Median progression-free survival was
cSCC, are weak and inconsistent and are limited by the 15 weeks. The authors concluded that although che­
small number of treated patients, heterogeneity of treat­ motherapy and/or cetuximab showed limited outcomes in
ment regimens, and different outcome assessments advanced cSCC, such therapy may be an option when
[148,152–157]. Platinum-based therapy has been used as anti-PD-1 treatment is contraindicated [158].
one of the standard chemotherapeutic options in the
management of advanced cSCC [126,138]. A systematic 10.3. Electrochemotherapy
review of mcSCC reported 60 cases treated with cisplatin
monotherapy published from 1989 to 2014, underlying the Electrochemotherapy (ECT) exerts its antitumour effect
paucity of data [138]. A complete response was described through the ability of high-voltage electric pulses to in­
in 22% and partial response in 23% of patients, resulting in crease the permeability (electroporation) of the cell mem­
an overall response of 45%. The median disease-free sur­ brane allowing intracellular access of chemotherapeutic
vival for patients who attained a complete response was drugs (bleomycin or cisplatin) that otherwise would not be
14.6 (range 3–112) months [138]. Polychemotherapies able to penetrate the cell effectively [159,160]. ECT has

Fig. 1. Proposed treatment algorithm for patients with cSCC. Strength of consensus: 90%. aFor detailed indications and recommendations
of treatment, refer to the relevant section text in the Guidelines. bLocally advanced by definition not amenable to curative surgery or RT.
c
Micrographically controlled surgery instead of sectional assessment is advised, when available. d Lymph node dissection as indicated. eIn
Europe, all systemic treatments are off-label, except for the anti-PD-1 agent cemiplimab that is approved by EMA for patients with
locally advanced or metastatic cSCC who are not candidates for curative surgery or curative radiotherapy. cSCC, cutaneous squamous
cell carcinoma; MCS, micrographically controlled surgery; RT, radiotherapy.
 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252 15

been used in patients with lacSCC, or with persistent or L1 < 1% demonstrated a pCR in contrast to 22/41 pa­
recurrent primary cSCC lesions when all other treatment tients with PD-L1 ≥ 1%. However, these results did not
options, including surgery and radiotherapy, failed or were reach statistical significance.
not feasible, if the patient refused any other treatments, Neoadjuvant cemiplimab appears as a very attractive
and as palliative care to relieve symptoms. Advantages alternative to immediate surgery. However, neoadjuvant
include a favourable response, particularly in small cemiplimab treatment is not yet approved by FDA
(< 3 cm) and non-ulcerated tumours [161], low toxicity, or EMA.
and preservation/improvement of quality of life. However,
there is limited evidence on the duration of local control 11.1.2. Adjuvant trials
and progression-free survival, as a short follow-up is re­ Cemiplimab is currently tested in an adjuvant clinical
ported. In a European study of ECT with bleomycin, the trial (REGN-1788, NCT03969004) in patients with
overall response rate in 156 patients with cSCC was 80%, cSCC at high risk of relapse. This trial (‘C-POST’) is a
and the complete response was 63%. The limitation of this randomised, placebo-controlled, double-blind, multi­
study was a short follow-up of 45 days due to the palliative centric phase 3 trial comparing cemiplimab to placebo
treatment setting [162]. In the InsPECT registry study, 162 after surgery and postoperative radiation. Cemiplimab
patients with primary, recurrent, or lacSCCs, were treated is initially used with the dose of 350 mg 3-weekly for 12
with ECT with bleomycin. Local response after 45–90 weeks followed by 700 mg 6-weekly for 36 additional
days of follow-up, included CR in 62% of patients, PR in weeks. The end-point of the trial is disease-free survival.
21%. At a mean follow-up of 8.6 months, 48.1% had no A very similar clinical trial of pembrolizumab in the
evidence of disease. The progression-free survival was adjuvant setting (KEYNOTE-630, NCT03833167) is
significantly lower for locally advanced compared to pri­ still actively recruiting patients. Patients with cSCC at
mary patients [163]. Another study from the InspECT high risk for recurrence are randomised after conven­
registry evaluated the ECT for skin cancers or cutaneous tional surgery and postoperative radiation to either
metastases in 61 elderly patients (> 90 years), who re­ pembrolizumab with 400 mg intravenously every 6
present a very frail population. After ECT, the objective weeks or matching placebo for 1 year. The end-point of
response in patients > 90 years was comparable to that this clinical trial is also disease-free survival.
observed in younger patients. These elderly patients were
managed with local/locoregional rather than general an­ 11.1.3. Intralesional cemiplimab
aesthesia [164]. A pilot phase 1 study on the intralesional use of cemi­
plimab was presented in May 2022 (Migden MR et al.,
11. Clinical trials 54th Annual Meeting of the American College of Mohs
Surgery, Philadelphia, May 2022; NCT03889912). In this
11.1. Trials with cemiplimab or pembrolizumab dose-finding study on cSCC patients with mainly skin
metastases, 250 µL per lesion with doses of 5–44 mg of
11.1.1. Neoadjuvant trials cemiplimab were intratumorally applied for consecutive 12
A neoadjuvant trial on cemiplimab for stage II–IV weeks, before definitive surgery was scheduled. A total of
cSCC patients (REGN-ONC-1901) was presented for 17 patients with a median age of 76 years and a pre­
the first time at ESMO 2022 and subsequently published dominance of primary cSCC on the head and neck region
[165]. In this clinical trial, 79 patients from Australia, (76%) have been included. Responses have been found at
Germany, and the US with a median age of 73 years all dose levels. 13/17 cSCC patients (76.5%) showed a
received four cycles of cemiplimab with a conventional complete response (pCR). Only one patient on the highest
dose (350 mg every 3 weeks intravenously) followed by cemiplimab dose level needed to discontinue the study
conventional surgery. The end-point of the clinical trial treatment due to adverse events. There was no treatment-
was the number of pathologically confirmed complete related death. Pruritus (23.5%) and fatigue (17.6%) were
responses (pCR) after a full resection of the tumour- the most common observed adverse events. The intrale­
containing area. Fifty-six percent of the patients showed sional use of cemiplimab appears as an attractive alter­
no viable tumour cells, another 12.7% a major patho­ native to conventional intravenous cemiplimab in selected
logical response with 1–10% viable tumour cells. The patients, although it is not yet approved by the FDA
pCR rate is clearly different compared to the radi­ or EMA.
ological response rates (ORR: 68.4%, CR: 6.3%), which
underestimate the magnitude of the cemiplimab benefit. 11.1.4. Oncolytic vaccines
There was one treatment discontinuation and four A new field of immunotherapies for advanced cSCC is
deaths (three unrelated to treatment by the investigator) the introduction of oncolytic vaccines with or without
during the trial. There was no correlation between the immune checkpoint inhibitors. Most oncolytic vaccines
tumour mutational burden and the pathological re­ are administered intratumorally to superficial and/or
sponse rate. There was a strong correlation between PD- deep cutaneous, subcutaneous, or visceral lesions, many
L1 expression (≥1%) with pCR. 3/15 patients with PD- via ultrasound or computer tomography guidance. They
16 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252

have been shown to be potent drugs acting by direct on 196 patients with a median age of 76 years has been
local killing of tumour cells and/or altering the tumour released at ESMO 2022 [169]. Most patients suffered
microenvironment. They aim to turn immunologically from locally advanced cSCC (63.3%), and the others
‘cold’ tumours with low numbers of tumour-infiltrating from metastatic cSCC (36.7%). 42.9% received prior
lymphocytes into ‘hot’ tumours, which are more sensi­ radiation therapy, 75% prior surgery, and 45.4% prior
tive to a systemic antitumour immune response. A systemic therapy, before they were included in the
randomised phase 3 trial used an oncolytic, genetically CASE study. The response rate of 37.4% included 9.8%
modified herpes simplex type I virus (CERPASS, RPL- complete responses. The disease control rate (DCR) was
002–18, NCT04050436) in 180 advanced cSCC patients 54.6%. Only five patients (2.6%) needed to discontinue
fully recruited by August 2022. This trial on a head-to- the treatment due to serious adverse events, one patient
head comparison of conventional cemiplimab to cemi­ died due to treatment-related pneumonitis.
plimab plus RP1 (oncolytic vaccine) has not released An international, observational, two-cohort, multi­
data, as of September 2022. centre study (‘CEMISKIN’) with a prospective and
The same oncolytic virus (RP1) is currently being retrospective cohort is currently ongoing in Germany,
used in anti-PD-1-naïve non-melanoma skin cancers Austria, and Switzerland. Roughly 70 study centres are
(NMSC) including cSCC and also PD-1-failed patients including patients with cemiplimab treatment for ad­
(IGNYTE, RPL-002–16, NCT03767348) [166]. In PD- vanced cSCC. This non-interventional study (NIS) has a
1-refractory patients, RP1 is combined with the PD-1 target of a total of 400 patients (200/cohort). The goal is
antibody nivolumab, and the first data were released at to assess the efficacy and tolerability of cemiplimab in a
ASCO 2022. Of 15 patients with cSCC who have been real-world setting.
treated with this combination 46.6% (n = 7) demon­ Rigosertib, a polo-like kinase 1 (PLK1) inhibitor, is
strated a complete response and two (13.2%) a partial being assessed in a phase II, open study in patients with
response. The median duration of response has not been recessive dystrophic epidermolysis bullosa associated
reached. with locally advanced/metastatic cSCC. (EudraCT
No.:2016-003832-19).
11.1.5. Combination of immunotherapy with EGFRi
Two trials focus on the combination of PD-1/PD-L1 12. Considerations of treatment in immunocompromised
antibodies and EGF-receptor inhibitors. The I- patients
TACKLE trial (NCT03666325) included 43 patients
with an advanced SCC. 16% of patients had received There is limited evidence from randomized controlled
prior chemotherapy and 49% prior radiotherapy [167]. trials and non-randomised studies to guide the manage­
The patients received pembrolizumab 200 mg every 3 ment of cSCC in immunocompromised patients. Close
weeks as first-line immune therapy and were switched dialogue and multidisciplinary decision-making shared
upon progression to a combination of pembrolizumab between patients, dermatologists, oncologists, surgeons,
with weekly cetuximab 250 mg/m2. 44% of patients had transplant clinicians, and other relevant health care
an objective response to pembrolizumab (CR: 12, PR: professionals are essential [170,171].
seven) of which four (21%) had a subsequent relapse.
Two of these patients were treated with pembrolizumab/ 12.1. Primary cSCC
cetuximab and both patients achieved a partial re­
sponse. 56% did not achieve an objective response on There is little prospective, randomised evidence to
first-line pembrolizumab (eight SD, 15 PD) and 21/23 suggest that primary cSCC in immunocompromised
patients received subsequent treatment with pem­ patients requires significantly different management
brolizumab/cetuximab. Eight patients (38%) achieved approaches to the general population [172,173].
an objective response (CR: three, PR: five) while 61% However, given the increased risk and potentially
did not (SD: eight, PD: five). atypical presentation and worse outcomes in im­
A clinical trial of the Alliance for Clinical Trials in munocompromised patients, the index of suspicion
Oncology in collaboration with the National Cancer for possible cSCC should be high, thresholds for
Institute (NCI) is currently treating advanced cSCC biopsy correspondingly low [170,174,175] and con­
patients with the PD-Ligand 1 antibody avelumab with firmed cSCC should be considered ‘high risk’ for the
and without cetuximab (NCT03944941). No data have purposes of management decisions (Stratigos 2023
been reported from this trial, as of September 2022. part 1) [2,176,177].
Surgery: It is usually recommended that high-risk
11.1.6. Other trials cSCC in immunocompromised patients requires more
The cemiplimab survivorship and epidemiology (CASE, aggressive surgery, but optimal excision margins and the
NCT03836105 [168]) trial is a prospective study on the role of MMS/intraoperative margin assessment are not
safety and efficacy of cemiplimab in patients with ad­ clearly established [170,173,178,179]. Few data exist on
vanced cSCC in the real-world setting. An interim result postoperative complications rates, including infection
 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252 17

and the need for prophylactic antibiotics [180]. Sir­ events may affect graft function and immunosuppressive
olimus appears to be associated with more frequent drugs may reduce the effectiveness of ICI therapy [198].
surgical dehiscence, but this does not usually justify its Data from approximately 40 OTRs with metastatic
discontinuation before surgery [178,181]. cSCC have been reported to date: disease control rates
Radiotherapy: Although radiotherapy is not the first range from 30% to 50%, with graft rejection in ap­
therapeutic option for most primary cSCC, particularly proximately 40% [188–193,195–202]. In all cases, par­
as immunocompromised patients are often younger and allel management of immunosuppression is likely to
may develop multiple primary cSCC within an anatomic play an important role in ICI responsiveness [198]. Re­
site, precluding its subsequent use at that site, it none­ ducing the risk of rejection by reducing or discontinuing
theless remains an important option when surgery is not immunosuppression or converting to mTOR inhibitors
appropriate [178]. is uncertain and has been questioned in melanoma [203].
There is some evidence that in metastatic cSCC it could
12.2. Locally advanced (LA) and metastatic be considered, as could the use of peri-infusional ster­
cSCC (mSCC) oids [197,201,204,205] and on the basis of current evi­
dence, it has recently been proposed that a dual
In immunocompromised patients with advanced cSCC, immunosuppressive regimen is maintained before ICI
there are specific considerations regarding the use of initiation by combining mTOR-inhibitors and either
checkpoint inhibitors, chemotherapy, and EGFR in­ corticosteroids or calcineurin-inhibitors [198]. This must
hibitors compared with immunocompetent patients and be considered in the context of allograft risk (rejection
the additional strategy of immunosuppression mod­ and its subsequent treatment) and risk of tumour pro­
ification in some cases [170,178,182]. Regarding con­ gression. Ultimately, a multidisciplinary approach
ventional chemotherapy, transplant-directed dosage should underpin all such clinical decision-making. En­
adjustment, close monitoring of allograft function, and couragingly, even after graft rejection due to ICI
potential interactions with drugs such as calcineurin therapy, successful re-transplantation has been reported
inhibitors and antiretroviral medications are important [206]. PD1 blockade for metastatic cSCC has also been
considerations in immunocompromised patients [182]. reported in people living with HIV and in patients with
Information on the use of anti-EGFR inhibitors such as haematological malignancies, although in the latter
cetuximab is limited to case reports [183–185]. Relevant group, disease control rates appear to be lower [194].
complications include neutropenia, infection, liver dys­ Prospective trials are now critically important to
function [182], and fatal pulmonary toxicity has been further establish the efficacy and safety of ICIs in im­
reported in lung transplant recipients treated with ce­ munocompromised patients and several are underway
tuximab [186]. (NCT04339062; NCT03816332). Further challenges for
Pivotal clinical trials of anti-PD1 immune checkpoint the future include understanding how to uncouple al­
inhibitor immunotherapy (ICI) excluded im­ loreactive immunity from anti-tumour immunity, bio­
munocompromised individuals [115,124] and informa­ marker identification for immunocompromised patients
tion on their safety and efficacy in these patients is likely to benefit from ICI therapy, and biomarkers for
restricted to case reports and retrospective series and a early detection of allograft rejection [198].
single phase I study [187]. Experience to date has been
mainly in immunocompromised patients with mela­ 12.3. Pre-transplant cSCC and re-transplantation
noma, but increasing data are now available for cSCC after cSCC
[188–197]. No consensus guidelines exist for the use of
ICI in immunosuppressed patients, and this should be Patients with a history of pre-transplant cSCC are in­
considered on a case-by-case basis in multidisciplinary creasingly common [174]. Consensus guidelines from the
consultation with the patient and their healthcare team. International Transplant Skin Cancer Collaborative
Key considerations include the high risk of allograft based on risk and kinetics of cSCC metastasis re­
rejection in organ transplant recipients (OTRs), the type commend that no waiting time is required for trans­
of allograft and the options for replacement therapy plantation after a low-risk cSCC and 2–4 years for high-
should the allograft fail, and the possibility that treat­ risk cSCC, depending on the status of perineural invasion
ment efficacy may be reduced by immune compromise. and other risk factors; 5 years waiting time is re­
However, based on current knowledge, it has been commended for cSCC with nodal metastasis and trans­
proposed that ICIs should be offered to kidney trans­ plantation is almost always contraindicated for distant
plant recipients with advanced cSCC if surgery and/or metastasis [170,174]. However, this is a rapidly changing
radiotherapy have failed and should be first-line ahead landscape as more effective treatments for advanced
of chemotherapy and targeted therapies [198]. cSCC become available [206]. The time to first cSCC is
The PD1 pathway is critical in maintaining allograft much shorter in OTRs with pre-transplant cSCC and
tolerance. In OTRs and PD1-blockade increases the risk similar to the interval between first and second cancers in
of allograft rejection [188]. ICI immune-related adverse those without pre-transplant cSCC [207]. The role of
18 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252

mTOR inhibitor-based maintenance immunosuppression applying zinc oxide paste or silicone gel on the surrounding
and chemoprevention with systemic retinoids in reducing skin. Slight bleeding can temporarily be stopped by
this risk is uncertain, but close surveillance is indicated the application of calcium alginate dressings, dressings with
[207]. For OTRs with a history of post-transplant cSCC xylometazoline or adrenaline (1:1000) or silver nitrate [219].
being considered for re-transplantation, the observed The Society of Integrative Oncology-ASCO guideline
increased risk of developing aggressive cSCC after a 2022 has provided evidence-based recommendations on
second transplant also needs to be considered [208]. integrative approaches to managing pain in patients
with cancer, including massage, acupuncture, reflex­
13. Best supportive care ology, or acupressure [220].

Although treatment options continue to expand for 14. Follow-up

cSCC, there is still a group of patients that cannot be
cured and is often left with a growing, ulcerated tumour. The prediction and identification of high-risk cSCC
Initially, palliative treatments like local surgery, RT, or patients that require strict surveillance are major is­
electrochemotherapy can be deployed to try to control sues in cSCC management due to the lack of clinically
tumour extension and relieve symptoms [209]. RT is relevant biomarkers or a staging system with a reliable
often used to relieve pain, stop haemorrhage, and to high predictive value [221,222]. A recent systematic
confine tumour expansion in functional areas like the review revealed significant inconsistency in the
eye or the facial nerve [210]. Hypo-fractionated schemes guidelines on follow-up of patients with cSCC and
(24–35 Gy in 3–6 fractions) or single dose (16–20 Gy) pointed towards the need of randomised clinical
can be applied depending on the location of the tumour, trials [223].
the performance status (physical and mental fitness) of cSCC typically affects elderly patients with multiple
the patient [210,211]. co-morbidities, Eastern Cooperative Oncology Group
If no further (palliative) treatments are desired or status commonly > 1 and often associated with multiple
possible, the focus of care is on quality of life. The pa­ tumours at different stages in the progression of kerati­
tient should be consulted about his/her individual nocyte skin cancer. Thus, the aims of follow-up in this
wishes, needs, and values. Supportive care includes special cohort of geriatric-oncologic patients differ in
wound care and pain management, nutritional, and some aspects from other types of cancers [7]. Certainly,
psychological support. Consultation with a palliative aims of follow-up of patients affected by high-risk cSCC
care team is advised [212]. included early detection of recurrence (both locally and
Quality of life can seriously be affected by pain and distant) and secondary cancers, clinically and radio­
should therefore be thoroughly tackled [213]. The ladder graphic assessment of response to treatment, evaluation
of the World Health Organisation is a helpful tool for of side-effects of medical treatment and education of
adequate pain management [214]. Paracetamol or non- patients and relatives. However, it should additionally
steroidal anti-inflammatory drugs are first-step pain re­ include the validation of the need of alternative, con­
lievers, followed by opioids. Application of morphine temporary treatments especially for patients with severe
gel can be of help in smaller wounds [215,216]. field cancerization and multiple primary cSCCs or for
To prevent malodour, the tumour should be rinsed daily OTRs [224,225]., and assessment of frailty, quality of life
with tap water or a disinfectant solution that contains so­ and life expectancy [226].
dium chloride solution of 0.9% or povidone iodine in a 2%
or 10% solution [217]. Silver and honey dressings are ef­
fective in reducing malignant fungating wound discharge 14.1. Definition of high-risk tumours/patients
and malodour [218]. Topical metronidazole or oral me­
tronidazole (250 mg, three times a day for 7–10 days) may Different staging systems and criteria have been em­
also be considered [219]. Maceration of the surrounding ployed to define high-risk cSCCs, and are detailed in
skin of the tumour because of exudate can be prevented by Part 1 of the guideline.

Box 14 Follow-up.

Consensus-based recommendation

GPP • cSCC patients shall be followed up for recurrences and development of new NMSC and melanoma.
• Follow-up in all patients shall include regular clinical examination, including inspection of the entire skin and inspection and
palpation of the excision site, the in-transit route and the regional lymph nodes, and advice on self-skin examination.
• Frequency of follow-up visits and imaging depends on underlying risk characteristics for cSCC patient: low-risk or high-risk
common primary, advanced or regional disease, immunosuppression setting (detailed in Table 3).
Strength of consensus: 100%.
Table 1
Response outcomes of prospective trials of anti-PD-1 therapy currently approved in Europe for the treatment in curative intent for advanced cSCC published from 2000 till 1 November 2022: Anti-
PD-1 agent cemiplimab.
Study Trial design, median follow-up Patients N cSCC type Treatment schema Response Survival
Migden, 2018 [115] Phase 1, open-label, multicentre 26 10 La Cemiplimab 3 mg/kg IV every 2 Best ORR 50% Not reported
11 months 8 regional weeks 13 PR Median duration of response: not
metastasis reached
8 distant
metastasis
Migden, 2018 [115] Phase 2, non-randomised, global, pivotal 59 14 regional Cemiplimab 3 mg/kg intravenously Best ORR 47.5% 1-year OS: not reached (estimated 81%)
study metastasis every 2 weeks 4 CR 1-year PFS: not reached (estimated 53%)
(Group 1) 45 distant 24 PR Median duration of response: not
7.9 months metastasis reached
Rischin, 2020 [119] 16.5 months Best ORR 49% Median PFS not reached Median
10 CR duration of response: not reached
19 PR
Rischin, 2021 [120] 18.5 months ORR: 51% Median duration of response: not
12 CR reached
18 PR
Rischin, 2020 [119] Phase 2, non-randomised study of the 56 12 regional Cemiplimab 350 mg intravenously Best ORR 41% Median PFS not reached Median
approved fixed-dose regimen metastasis every 3 weeks 3 CR duration of response: not reached
(Group 3) 43 distant 20 PR
8.1 months metastasis
Rischin, 2021 [120] 17.3 months ORR: 42.9% Median duration of response: not
9 CR reached
15 PR
Migden, 2020 [121] Phase 2, non-randomised, global, pivotal 78 78 La Cemiplimab 3 mg/kg intravenously ORR 44% 1-year DFS: 87.8%
study every 2 weeks CR 13% Median duration of response: not
(Group 2) PR 31% reached
A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252

9.3 months
Rischin, 2021 [120] 15.5 months ORR: 44.9% Median duration of response: not
10 CR reached
25 PR
CR, complete response; DCR, disease control rate (CR + PR + SD); DSS, disease-specific survival; m, months; ORR, overall response rate (CR + PR); OS, overall survival; PD, progressive
disease; PFS, progression-free survival; PR, partial response; SD, stable disease; w, weeks.
19
20 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252

Table 2
Response outcomes and dosing regimens of prospective studies of EGFRi for treatment of advanced cSCC published from 2000 till 1
November 2022.
Reference Trial design Patients N cSCC type Treatment regiments Response Survival
Anti-EGFR antibodies
Maubec, 2011 Phase II open-label, 36 33 unresectable Cetuximab ORR: 28% Mean OS: 8.1 m
uncontrolled, 3 metastatic Initial dose of 400 mg/m2 followed DCR: 69% Median PFS: 4.1 m
multicentre trial by weekly doses of 250 mg/m2 for at 2 CR 8 PR
least 6 w
Preneau, 2014 Open label, single- 20 La 6 Cetuximab ORR: OS: 11.1 m
centre, non- Initial dose of 400 mg/m2 followed C: 33% C: 2.5
randomised by weekly doses of 250 mg/m2 C-C: 37.5% C-C: 5.6
9 Cetuximab as above + C-RT: 80% C-RT: 3
Carboplatin 300 mg/m2 monthly DCR: PFS: 5.7 m
5 Cetuximab + RT C: 50% C: 1.3
Cetuximab as above, RT: 60–70 grey C-C: 87.5% C-C: 2.8
C-RT: 100% C-RT: 1.6
Joseph, 2018 Single-centre 8 Inoperable Cetuximab + RT 6 CR 2-y PFS: 83.3%
Cetuximab at Initial dose of 400 mg/ 1 PR 2-y SSS: 87.5%
m2 7 days prior to RT, followed by 1 PD
weekly doses of 250 mg/m2 for the
duration of RT
Foote, 2014 Phase II, 16 14 la Panitumumab ORR: 31% Median OS: 11 m
uncontrolled, single- 2 metastatic 6 mg/kg every 2 weeks for Median PFS: 8 m
centre trial a maximum of 9 cycles
EGFR tyrosine kinase inhibitors
William, 2017 Phase II, uncontrolled 40/37 27 locoregionally Gefitinib ORR 16% Median OS: 12.9 m
evaluable recurrent 250 mg/day orally ORR in Median PFS: 3.8 m
4 la mcSCC: 0
9 metastatic DCR 51%
Gold, 2018 Phase II, 29 Locoregionally Erlotinib ORR 10% Median OS: 13 m
uncontrolled, single- recurrent or 150 mg/day orally DCR 72% Median PFS: 4.7 m
centre metastatic cSCC (dose reduction management 3 PR, 18
specified in the study) SD, 8 PD
C, cetuximab monotherapy; C-C, cetuximab combined with carboplatin; CR, complete response; C-RT, cetuximab combined with
radiotherapy; cSCC, cutaneous SCC; DCR, disease control rate (CR+PR+SD); la, locally advanced; m, months; mcSCC, metastatic
cSCC; ORR, overall response rate (CR+PR); OS, overall survival; PD, progressive disease; PFS, progression-free survival;
PR, partial response; SD, stable disease; SSS, scc-specific survival; w, weeks.

14.1.1. Risk assessment for local recurrence patients (98.1%) with nodal disease received therapy
Based on current available literature, the highest risk for (surgery, radiotherapy and/or chemotherapy) aimed at
local and distant recurrence appears within the first 2 treating nodal disease. Eighteen of 26 patients (69%)
years after diagnosis of a primary cSCC [227]. First site developed distant metastases following previously ad­
of metastatic spread appears in the lymph node, thus juvant treated isolated nodal disease surveillance, while
follow-up both clinically and radiologically should focus eight of 26 (31%) had concomitant nodal and distant
on these sites. Special attention is required for patients metastatic disease at follow-up, with subsequent con­
with immunosuppression such as haematological co- firmation of cSCC as the metastasis source [227].
morbidities or iatrogenic immunosuppression (OTR or
others), who were reported to develop regional lymph 14.1.3. Risk assessment for multiple tumours
node metastases 6.7 months after diagnosis of the pri­ Patients with multiple cSCCs are at higher risk for nodal
mary tumour [228]. disease and local recurrence. Thus, patients with mul­
tiple tumours (> 2–10 tumours) would benefit form close
14.1.2. Risk assessment for distant metastases surveillance programs, especially when associated with
In a large study evaluating 3455 tumours in 2522 pa­ immunosuppression [229].
tients, 116 (4.5%) patients developed nodal metastasis
and 26 patients with nodal disease developed radi­ 14.1.4. Risk assessment in immunocompromised patients
ologically confirmed distant metastasis. The mean time Solid organ transplant recipients (SOTRs) have a 100-
to first nodal metastasis were 0.83 (1.29) and 0.98 (1.18) fold increased risk of cSCC, and they may develop more
years, and 26 of 105 (24.8%) and eight of 26 (31%) pa­ aggressive cSCCs compared with immunocompetent
tients were immunosuppressed. In total, 103 of 105 individuals. It has been shown that close dermatological
 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252 21

cell
Society for Radiotherapy and Oncology;

been consistently studied, an individual risk

surveillance along with field-related treatments may re­

According to the characteristics of individual cSCC

duce an aggressive course of disease [230].

squamous
Based on the
The dilemma in providing clinically relevant and re­
liable evidence-based follow-up guidelines for cSCC are

response
related to the lack of studies evaluating the hetero­

4+
geneous characteristics of patients affected by cSCC.

-
-

cutaneous
Medical Specialists.
15. Communication with the patient

3–6 m
3
-
-
When diagnosing common primary cSCC, the clinician

CT, MRI, PET/CT

advanced
will need to give information about the type of cSCC di­

3–6 m
agnosed and the risk of relapse or metastasis. Patients

2
-
-
should be reminded that most cSCCs are well-differ­

carcinoma; mcSCC, metastatic cSCC; m, months; MRI, magnetic resonance imaging; PET, positron emission tomography; UEMS, European Union of
High-risk cSCC patient as defined by EADO guidelines (Stratigos et al. Part 1). As the independent prognostic effect of high-risk factors has not
CT, computed tomography; EADO, European Association of Dermato-Oncology; EDF, European Dermatology Forum; ESTRO, European
entiated tumours, which have a low risk of recurrence and/

3–6 m

locally
or metastasis. Patients may need support from clinical

1
-
-
nurse specialists in cases of disfiguring surgery or the de­
livery of bad news and need to be offered access to support

According to the characteristics of individual cSCC

lacSCC,
services when deemed necessary. Self-examination should

Consensus-based proposal for follow-up schedule for patients with history of cSCC proposed by EADO-EDF-ESTRO-UEMS-EORTC.

6–12 m
be discussed for the diagnosis of new primaries and de­

Ultrasound of lymph nodes or parotid gland

6+
tection of lymph nodes in the draining basins.

-
-

immunosuppressed;
Patients with SCCs should also be informed of dif­
ferent treatment modalities, and these need to be dis­

3–6 m
cussed when appropriate with the patient/family/

3–5
caregiver. The potential consequences of foregoing

-
-
treatment should also be explained. Patients should be
made aware that radiotherapy could not be the best
3–6 m
3–6 m
treatment option in young age groups as radiotherapy

IS,
2
-

scars could worsen over time and there is a risk of sec­

ondary malignancies, although it is very low.

Follow-up will also depend on individual symptoms and response to treatment. Consensus: 100%.

Cancer;
Surgery for high-risk tumours should not be less than
3–6 m
3–6 m

optimal in elderly patients as the consequences of not

1
-

offering optimal treatments in a timely manner may lead

to difficult tumours to manage with subsequent mor­ of
bidity and possible impact on mortality. However, it is
Treatment
Every 3–6 m lifelong + according to the characteristics
6–12 m

important to consider the patient’s morbidities and

12 mb

OTR, chronic lymphocytic leukaemia or with xeroderma pigmentosum.

treatments options are always discussed with the pa­
6+
-

tient, their family, or carers even after multidisciplinary

discussions.
and

An information leaflet should be provided giving

12 mb

facts about SCCs and these tumours are the second

3m
3–5

Research
-

most common skin cancer after basal cell carcinomas.

Clinical/physical examination

Risk factors should be explained such as chronic sun

assessment is advised to guide follow-up decisions.

exposure, genetic and host factors such as fair skin,

3–6 m

immunosuppression, or the presence of syndromes with

12 m

for
3m

increased susceptibility to skin cancers such as xer­

2

Based on individual risk factor profile.

oderma pigmentosum and albinism. In patients with

Organisation

cSCCs and family history of uterus and/or bowel cancer,

of cSCC

clinicians should discuss genetic counselling and testing

3–6 m
12 m

3m

for DNA mismatch repair genes to rule out Lynch or

1

Hereditary Non-Polyposis Colon Cancer (HNPCC)

syndrome. If the gene mutation is confirmed, the patient
European

will be offered colon and uterus cancer screening, and it

lacSCC or
High riska
Year of follow-up
cSCC Low risk

is important that these patients are managed by cancer

mcSCC

geneticists and other specialists.

ISc

Patients may have different types of follow-up sche­

EORTC,
Table 3

dules depending on age, location of tumour, histological

b
c
a

subtype, previous primaries, recurrences, and other host

22 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252

factors such as immunosuppression. The risk of recur­ A qualitative study looked at the needs and pre­
rence should be discussed taking account of the tumour ferences of patients with cSCC regarding treatment and
characteristics and other risk factors. Patients should be follow-up care: Patients mentioned that clear informa­
advised how to perform self-examination. For im­ tion on self-inspection would reduce the need for follow-
munosuppressed patients, it is recommended that pa­ up visits and that they wished information preferably on
tients are followed up for life, ideally in dedicated clinics paper. Patients preferred periodic follow-up visits with a
with experience in the management of these complex possibility to come in-between visits in case of suspi­
patients. Patients will also need advice about sun pro­ cious new lesions and believed it was too hard to self-
tection and how to use treatments for field cancerization detect cancer or make self-skin examination of the
at home with topical products if appropriate. whole body [231].

Summarising box of recommendations

Practice points Recommendation GOR

1. Surgical excision of primary cSCC Surgical excision with histological control shall be performed as standard treatment. The aim A
of cSCC surgery shall be a complete excision (R0) with histological confirmation of peripheral
and deep excision margins.
Large tumours or tumours on the head and neck can undergo a punch or incisional biopsy for
histological confirmation and planning of a subsequent complete excision.
In cases of positive margins, a re-excision shall be done, for operable cases.
2. Surgery and safety margins Low-risk cSCC should be excised with a clinical safety margin of 5 mm. B
cSCC with high-risk factors should be excised with a clinical safety margin of 6–10 mm or by
micrographically controlled surgery.
Micrographically controlled surgery should be considered for cSCC in functional/cosmetical
sensitive areas.
3. Wound closure As long as an R0 resection is not histologically confirmed, wound closure with local tissue GPP
movements (flaps) should be avoided.
4. Therapeutic lymph node dissection A regional therapeutic lymph node dissection should be performed in patients with lymph B
node metastasis detected clinically or by imaging tests and confirmed with cytology or biopsy.
The extent of surgical resection is determined by the surgeon in collaboration with the
multidisciplinary tumour board.
5. Elective lymph node dissection for N0 Elective lymph node dissection shall not be performed for N0 cSCC. X
cSCC
6. Elective neck lymph node dissection for Elective neck dissection may be discussed and offered for metastatic cSCC within the parotid. C
mcSCC to the parotid
7. Destructive modalities for cSCC Destructive modalities such as ED & C, cryotherapy, PDT, and lasers should not be performed GPP
in the treatment of primary invasive cSCC. Exceptions can be considered in small-sized and/or
multiple cSCCs in low-risk areas where surgery and/or RT are not possible or have
unacceptable consequences.
8. Definitive primary RT Primary radiotherapy should be considered as an alternative to surgery for inoperable or B
difficult-to-operate tumours or in the absence of consent to surgical excision.
9. Postoperative RT Postoperative radiotherapy should be considered after surgical excision for cSCC with positive B
margins and for which re-excision is not possible.
10. Adjuvant RT for resected nodal meta­ Adjuvant radiotherapy following therapeutic lymphadenectomy should be considered in cSCC B
static cSCC of the head and neck with regional nodal metastases and extracapsular extension.
11. Adjuvant RT for high-risk cSCC Adjuvant radiotherapy may not be offered as standard of care for cSCC with clear surgical C
margins, as a clear benefit has not been shown.
12. Immunotherapy for advanced cSCC Patients with metastatic cSCC or locally advanced cSCC, who are not candidates for curative B
surgery or curative radiation, should receive first-line treatment with a PD-1 antibody*.
13. EGFR inhibitors Cetuximab may be used for patients with locally advanced and metastatic cSCC, who have C
failed to respond or are intolerant to immunotherapy. Cetuximab combined with RT is
favoured over cetuximab monotherapy.
14. Follow-up cSCC patients shall be followed up for recurrences and development of new NMSC and GPP
melanoma.
Follow-up in all patients shall include regular clinical examination, including inspection of the
entire skin and inspection and palpation of the excision site, the in-transit route and the
regional lymph nodes, and advice on self-skin examination.
Frequency of follow-up visits and imaging depend on underlying risk characteristics for cSCC
patient: low-risk or high-risk common primary, advanced or regional disease, immunosup­
pression setting (detailed in Table 3).

cSCC, cutaneous squamous cell carcinoma; GOR, grade of recommendation; GPP, good practice point; NMSC, non-melanoma skin cancer;
RT, radiotherapy.
*In Europe, cemiplimab is currently the only approved medication, while pembrolizumab and nivolumab are investigated in clinical trials
 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252 23

Funding sources Review & Editing, Supervision. Petr Arenberger:

Conceptualization; Writing - Review & Editing,
The development of the current set of guidelines was Supervision. Alexander M. M Eggermont :
supported solely by funds of the EADO which were Conceptualization; Writing - Review & Editing,
used to mainly support the consensus meeting Supervision. Martin Rocken: Conceptualization; Writing -
without honoraria and without reimbursement of Review & Editing, Supervision. Jean-Jacques Grob:
travel costs. Conceptualization; Writing - Review & Editing,
Supervision. Paul Lorigan: Conceptualization; Writing -
CRediT authorship contribution statement Review & Editing, Writing - Original Draft, Supervision.

Alexander J. Stratigos: Conceptualization; Writing - Declaration of Competing Interest

Review & Editing, Writing - Original Draft, Supervision.
Claus Garbe: Conceptualization; Writing - Review & The authors declare the following financial interests/
Editing, Writing - Original Draft, Supervision. Clio personal relationships which may be considered as po­
Dessinioti: Conceptualization; Writing - Review & tential competing interests:
Editing, Writing - Original Draft, Supervision. Celeste
1. Dr. Stratigos reports personal fees and/or research support
Lebbe: Conceptualization; Writing - Review & Editing,
from Novartis, Roche, BMS, Abbvie, Sanofi, Regeneron,
Supervision. Alexander van Akkooi: Conceptualization; Genesis Pharma, outside the submitted work.
Writing - Review & Editing, Supervision. Veronique 2. Dr. Garbe reports personal fees from Amgen, personal fees
Bataille: Conceptualization; Writing - Review & Editing, from MSD, grants and personal fees from Novartis, grants
Supervision. Lars Bastholt: Conceptualization; Writing - and personal fees from NeraCare, grants and personal fees
Review & Editing, Supervision. Brigitte Dreno: from BMS, personal fees from Pierre Fabre, personal fees
Conceptualization; Writing - Review & Editing, from Philogen, grants and personal fees from Roche,
Supervision. Reinhard Dummer: Conceptualization; grants and personal fees from Sanofi, outside the sub­
Writing - Review & Editing, Supervision. Maria Concetta mitted work.
Fargnoli: Conceptualization; Writing - Review & Editing, 3. Dr. Dessinioti has nothing to disclose.
4. Dr. Lebbe reports grants and personal fees from Bristol-
Supervision. Ana Maria Forsea: Conceptualization;
Myers Squibb, personal fees from MSD, personal fees
Writing - Review & Editing, Supervision. Catherine Α.
from Novartis, personal fees from Amgen, grants and
Harwood: Conceptualization; Writing - Review & Editing, personal fees from Roche, personal fees from Avantis
Supervision. Axel Hauschild: Conceptualization; Writing - Medical Systems, personal fees from Pierre Fabre, per­
Review & Editing, Supervision. Christoph Hoeller: sonal fees from Pfizer, personal fees from Incyte, outside
Conceptualization; Writing - Review & Editing, the submitted work.
Supervision. Lidija Kandolf-Sekulovic: Conceptualization; 5. Dr. Bataille reports personal fees from Novartis, personal
Writing - Review & Editing, Supervision. Roland fees from Merck MSD, outside the submitted work.
Kaufmann: Conceptualization; Writing - Review & 6. Dr. Bastholt reports personal fees for advisory board ac­
Editing, Supervision. Nicole WJ Kelleners-Smeets: tivity: BMS, Roche, Novartis, Pierre-Fabre, Astra Zeneca,
Conceptualization; Writing - Review & Editing, InCyte, MSD/Merck, Bayer, outside the submitted work.
7. Dr. Dréno reports grants and personal fees from BMS,
Supervision. Aimilios Lallas: Conceptualization; Writing -
personal fees from MSD, grants and personal fees from
Review & Editing, Supervision. Ulrike Leiter:
Roche, grants and personal fees from Fabre, grants and
Conceptualization; Writing - Review & Editing, personal fees from Sanofi, outside the submitted work.
Supervision. Josep Malvehy: Conceptualization; Writing - 8. Dr Dummer reports intermittent, project focused con­
Review & Editing, Supervision. Veronique del Marmol: sulting and/or advisory relationships with Novartis, Merck
Conceptualization; Writing - Review & Editing, Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS),
Supervision. David Moreno-Ramirez: Conceptualization; Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma,
Writing - Review & Editing, Supervision. Giovanni Sanofi, Catalym, Second Genome, Regeneron, Alligator,
Pellacani: Conceptualization; Writing - Review & Editing, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME
Supervision. Ketty Peris: Conceptualization; Writing - outside the submitted work.
Review & Editing, Supervision. Philippe Saiag: 9. Dr. Fargnoli reports personal consulting fees from
Almirall, honoraria from Sanofi-Regeneron and partici­
Conceptualization; Writing - Review & Editing,
pation in Advisory Board for Sanofi-Regeneron, outside
Supervision. Luca Tagliaferri: Conceptualization; Writing
the submitted work.
- Review & Editing, Supervision. Myrto Trakatelli: 10. Dr. Forsea reports scientific consultant/speaker fee from
Conceptualization; Writing - Review & Editing, Novartis, Merck, outside the submitted work.
Supervision. Dimitrios Ioannides: Conceptualization; 11. Dr. Harwood reports institutional research grants and
Writing - Review & Editing, Supervision. Ricardo Vieira: honoraria from Sanofi, Novartis, Merck, Pfizer,
Conceptualization; Writing - Review & Editing, Galderma, MEDA, Almirall, Pellepharm, Leo Pharma,
Supervision. Iris Zalaudek: Conceptualization; Writing - CERIES, outside the submitted work.
24 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252

12. Dr. Hauschild reports grants and personal fees from 25. Dr. Eggermont reports over the last 5 years personal fees as a
Amgen, grants and personal fees from BMS, grants and consultant advisor for Biocad, BioInvent, Bristol Myers
personal fees from MerckPfizer, grants and personal fees Squibb (BMS), CatalYm, Ellipses, Glaxo Smith Kline
from MSD/Merck, grants and personal fees from (GSK), HalioDX, Incyte, IO Biotech, ISA Pharmaceuticals,
Philogen, grants and personal fees from Pierre Fabre, Merck Sharpe & Dohme (MSD), Novartis, Pfizer,
grants and personal fees from Regeneron, grants and Polynoma, Regeneron, Sanofi, Sellas, SkylineDx. Alexander
personal fees from Roche, grants and personal fees from M.M. EGGERMONT: Honoraria, consultancy, SAB,
Sanofi-Genzyme, grants and personal fees from Novartis IDMC, lectures for the last 2 years: Agenus, BioInvent,
Pharma, grants and personal fees from Eisai, personal fees BioNTech, BMS, Brenus, CatalYm, Clover Pharmaceuticals,
from Immunocore, grants and personal fees from Ellipses, Galecto, GenOway, GSK, IO Biotech, IQVIA, ISA
Replimune, personal fees from Seagen, personal fees from Pharmaceuticals, Merck&Co/MSD, Pierre Fabre, Pfizer,
IO Biotech, personal fees from Dermagnostix, personal Sairopa, Sellas, SkylineDx, TigaTx, Trained Therapeutics,.
fees from Incyte, grants and personal fees from NeraCare, Equity: IO Biotech, Sairopa, SkylineDX.
personal fees from Highlight Therapeutics, grants from 26. Dr. Grob reports personal fees for advisory board and as
Huya Biosciences, personal fees from Kyowa Kirin, out­ speaker from Amgen, Roche, GSK, Novartis, BMS, Pierre
side the submitted work. Fabre, Merck, Sanofi, Merck, Pfizer outside the sub­
13. Dr. Hoeller reports personal fees from BMS, personal fees mitted work.
from Novartis, grants and personal fees from Amgen, 27. Alexander van Akkooi: Advisory Board / Consultancy
personal fees from Almirall, personal fees from Pierre Honoraria: Amgen, Bristol-Myers Squibb, Novartis,
Fabre, personal fees from Sanofi, personal fees from MSD, MSD-Merck, Merck-Pfizer, Pierre Fabre, Provectus,
outside the submitted work. Sanofi, Sirius Medical, 4SC.
14. Dr. Kandolf-Sekulovic reports speakers’ honoraria for 28. Dr Lallas has nothing to disclose.
Roche, Novartis, MSD, BMS, Janssen outside the sub­ 29. Dr Ioannides reports support from Sanofi in a phase III
mitted work. clinical trial, outside the submitted work.
15. Dr. Kaufmann reports institutional research grants (clinical 30. Dr Lorigan reports honoraria (consulting/advisory/
trials) from: AbbVie, Amgen, Biontech, BMS, Celgene, speakers’ bureau) from BMS, Merck/MSD, Nektar,
Galderma, Janssen, Leo, Lilly, Merck, MSD, Novartis, NeraCare, Amgen, Novartis, Oncology Education
Pierre Fabre, Pfizer, Regeneron, Roche, Wyeth. Advisory Canada, Pierre Fabre, Roche, outside the submitted work.
Board and Honoraria from Merz, Roche, Novartis, out­ 31. Dr Rocken reports study grants from AB Science, Abbott,
side the submitted work. Abbvie, Alcedis, Almirall Hermal, Amgen, AnaptysBio, ar­
16. Dr. Kelleners-Smeets reports grants from Netherlands genx, AstraZeneca, Bayer, Biogen idec, Boehringer Ingelheim,
Organization for Health Research and Development, Bristol-Myers Squibb, Celgene, CureVac, DelArrivo, Dynavax
other from Janssen-Cilag, other from AbbVie, other from Technologies, Eli Lilly, Galderma, Genentech, GSK,
Galderma, outside the submitted work. Hoffman-La Roche, Hokusai, Idera Pharmaceuticals, Ilkos
17. Dr. Malvehy reports research grants from Almirall, Therapeutic, Immatics Biotechnologies, Incyte, Iovance
ISDIN, Leo Pharma, Galderma, GSK, Cantabria; parti­ Biotherapeutics, Janssen-Cilag, Johnson & Johnson, LEO
cipation in advisory board meetings for Almirall, Pharma, Merck, MSD Sharp & Dome, Novartis
Sunpharma, BMS, Roche, Novartis, Pierre-Fabre, outside Pharmaceuticals, PellePharma, Pfizer, Philogen, Regeneron
the submitted work. Pharmaceuticals, Sanofi-Aventis, Schering-Plough, Sun
18. Dr. del Marmol reports personal fees from MSD, from Pharma, Technische Universitat Dresden, Topaz Therapeutics,
BMS, personal fees from Sanofi, grants and personal fees UCB, Universitatsklinikum Essen, Universitatsklinik Koln,
from ABVIE, grants from Jansen, outside the sub­ 4SC, grants for research projects from Deutsche
mitted work. Forschungsgemeinschaft, Deutsche Krebshilfe, Wilhelm
19. Dr. Moreno-Ramírez has nothing to disclose. Sander-Stiftung, consulting fees from Galderma, support for
20. Dr. Pellecani reports grants from university of Modena attending meetings/travel from EADV, International League
and Reggio Emilia, during the conduct of the study; grants of Dermatological Societies, patent PCT/EP2020/072203, stock
from Novartis, grants and personal fees from Almirall, or stock options from Bristol-Myers Squibb, CureVac, Merck,
grants from Leo Pharma, from null, outside the sub­ Pfizer, outside the submitted work.
mitted work. 32. Dr Arenberger has nothing to disclose.
21. Dr. Peris reports honoraria for advisory board and grants 33. Dr Tagliaferri reports honoraria from Elekta, Igea
from AbbVie, Almirall, Biogen Celgene, Lilly, Galderma, Medical, SunPharma, Sanofi, Roche, Molipharma,
Leo Pharma, Novartis, Roche, Sanofi, Sun Pharma, Nanobiotix, Novartis, outside the submitted work.
Sandoz outside the submitted work. 34. Dr Leiter reports personal fees from MSD, honoraria from
22. Dr. Saiag reports honoraria for advisory board and grants MSD, Novartis, Sun Pharma, Sanofi, Almiral Hermal, support
from Amgen, Bristol-Myers Squibb, MSD, Merck-Serono, for attending meetings/travel from Pierre Fabre, Sun Pharma,
Novartis, Pfizer, Roche-Genentech, Pierre Fabre, and participation in Advisory Board for MSD, Novartis, Sun
Sanofi, outside the submitted work. Pharma, Sanofi, Almiral Hermal, outside the submitted work.
23. Dr. Vieira has nothing to disclose. 35. Dr Trakatelli reports travel grants from Janssen, UCB,
24. Dr. Zalaudek reports honoraria and advisory board and Abbvie, honoraria from UCB, Genesis Pharma, Pierre Fabre
grants from Sanofi, Sun Pharma, Novartis, Galderma, Greece, EADV courses, travel expenses for congresses from
Roche, Celgene, Almirall, Leofarma, Mylan, Difa Cooper, Abbvie, Pierre Fabre Greece, Genesis Pharma, outside the
Cieffe Labs, La Roche Posay, Pierre Fabre. submitted work.
 A.J. Stratigos et al. / European Journal of Cancer 193 (2023) 113252 25

Acknowledgements clinical practice guidelines in oncology. Squamous Cell Skin

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