Current Treatment Options in Oncology (2014) 15:302–320

DOI 10.1007/s11864-014-0280-x

Skin Cancer (WH Sharfman, Section Editor)

Therapy of Advanced
Squamous Cell Carcinoma
of the Skin
Claudia Bejar, MD
Eve Maubec, MD, PhD*
Address
*AP-HP, Groupe Hospitalier Bichat Claude Bernard, Service de Dermatologie,
Université Paris Diderot, PRES Sorbonne Paris Cité,
46 rue Henri Huchard, Paris, Cedex, 75877, France
Email: eve.maubec@inserm.fr

Published online: 19 March 2014

* Springer Science+Business Media New York 2014

Keywords Squamous cell carcinoma of the skin I Chemotherapy I Immunotherapy I Targeted therapy I Epidermal
growth factor receptor I Inhibitors of the PI3K/AKT/mTOR pathway I NOTCH

Opinion statement
Advanced unresectable squamous cell carcinoma of the skin (SCCS) is a rare condition,
which is difficult to treat. Because of its rarity, few therapeutic trials are available.
Moreover, SCCS often occur in elderly. Conventional treatment options for advanced
SCCS are chemotherapy mainly with cisplatin-based regimens. Immunotherapy with in-
terferon alpha and retinoids combination was also shown to be efficient. Toxicity of
these treatments limits, however, their use in elderly patients and an initial work up
for a global assessment is needed in order to adapt the choice. More recently, epithelial
growth factor receptor (EGFR) targeted therapies have been developed and induced in-
teresting response rates in small series of patients with unresectable SCCS. Their effi-
cacy in SCCS must be confirmed by larger phase III trials and the identification of
predictive biological factors of response is warranted. New therapeutic approaches
combining EGFR inhibitors either with IGFR inhibitors, or immunomodulators or inhib-
itors of the PI3K/AKT/mTOR pathway are currently under evaluation in head and neck
carcinomas and might represent valuable therapeutic approaches for unresectable
SCCS. Moreover, there are several new molecular candidate treatment targets for
unresectable SCCS including somatic NOTCH1 or NOTCH2 inactivating mutations,
ALK1, which could be a good candidate for antiangiogenic therapy and matrix
metallopeptidase 7, which enhances proliferation, migration, and invasion of cancer
cells. Organ transplant recipients often develop SCCS and in some patients, SCCS are
rapidly progressing. Management of SCCS in this subgroup of patients includes both
carcinologic treatment and modification of immunosuppression. Specific treatment is
generally the same as in immunocompetent patients. Switching from calcineurin inhib-
itors to sirolimus or reducing immunosuppression has to be considered.
 Therapy of Advanced Squamous Cell Carcinoma of the Skin Bejar and Maubec 303

Introduction
Squamous cell carcinoma of the skin (SCCS) is the sec-
ond most common form of skin cancer, and the inci-
dence has continued to increase over the last decades
[1]. SCCS often occurs in elderly and immunosup-
pressed patients. Main risk factors for SCCS are sun ex-
posure, light phototype, and immunosuppression.
Human papillomavirus infection has also been associ-
ated with SCCS. Aging population, increase of organ-
transplant recipients, and evolution of attitudes to-
ward UV exposure contribute to the increase in the in-
cidence of SCCS [2]. In 2007, the number of deaths
caused by SCCS in North America has been estimated
to be 2500 [3]. Although the initial treatment achieves
overall cure rates of 95 %, a minority (4 %–10 %) of
SCCSs recur locally or metastasize usually to regional
lymph nodes or rarely to distant locations accounting
for 20 % of deaths related to skin cancer [3–5].
Some prognostic factors for recurrence and risk of
metastasis are part of the AJCC 2010 staging [2]: tu-
mors of a diameter greater than 2 cm, high-risk loca-
tions (lip, ear), presence of lymph node metastasis,
deep invasion of bone, perineural invasion, histologic
thickness greater than 2 mm, or Clark level≥IV, and
poor degree of differentiation. Several other risk fac-
tors of poor prognosis are not included in the AJCC
classification: desmoplastic growth [5], epidermolysis
bullosa and other chronic dermatosis [6, 7], and im-
munosuppression. There is an increased risk of SCCS
in HIV-positive patients [8] and SCCS are the most
common tumors after organ transplantation [9]. In
this population, the risk of SCCS is increased 100-fold,
SCCS are often evolutive, and the overall rate of me-
tastasis per patient exceeds 10 percent [10]. The role
of immunosupressive medications on the incidence
of SCCS has been demonstrated. Anticalcineurins,
which are frequently used as part of immunosuppres-
sive therapy, are involved in the onset and spread of
tumors [11, 12].
These high risk SCCS have a rate of recurrence or
metastasis of 20 %–25 % during the first 2 years after
diagnosis [2, 13, 14].
Advanced SCCSs are defined as (1) locally
unresectable advanced tumor deeply invasive involv-
ing muscle, nerve, or bone structures; (2) unresectable
regional lymph node disease; and (3) occurrence of
multiple distant metastases.

Treatment
Conventional treatment options for advanced SCCS are either cytotoxic
chemotherapies with mainly cisplatin based chemotherapies, or immu-
notherapy with interferon alpha combined with retinoids (Table 1).
More recently, EGFR-targeted therapies have been developed. Because of
the relative rarity of advanced SCCS, few prospective trials are available.
These trials consist often of phase 2 studies and, as distant metastasis
are rare, they include mainly cases of locally and regionally advanced
disease.

Conventional chemotherapy
Cisplatin and bleomycin

& Denic et al. [15] have reported 3 patients with SCCS who were
treated before surgery with 3 cycles of cisplatin 20 mg/m2 daily
for 4 days and bleomycin 20 mg/day for 4 days by continuous
infusion every 3 weeks. One patient with a complete response
(CR) and another with a partial response (PR) could undergo
surgery.
304 Skin Cancer (WH Sharfman, Section Editor)

Table 1. Chemotherapy and immunotherapy trials in SCCS

Authors Number Treatments Number of Trial

of patients patients with design
included/ response
evaluables (CR/PR)
Cisplatin based chemotherapies
Denic et al. [15] 3/3 Cisplatin (20 mg/m2) + bleomycin 2 (1/1) Case series
(20 mg/d 4 d)
Guthrie et al. [16] 3/3 Cisplatin (75 mg/m2) + doxorubicin 2 (1/1) Case series
(50 mg/m2)
Guthrie et al. [17] 12/12 Cisplatin (75 mg/m2) + doxorubicin 7(4/3) Prospective
(50 mg/m2) trial
Sadek et al. [18] 14/13 Cisplatin 100 mg/m2 D1, 11 (4/7) Prospective
5-FU 650 mg/m2/d D1–D5, trial
bleomycin IV bolus of 15 mg D1,
bleomycin 16 mg/ m2/d D1–D5
Khansur et al. [19] 7/7 Cisplatin (100 mg/m2 d1) +5-FU 6 (3/3) Case series
1 g/m2/d d1–d4
Other Chemotherapies
Cartei et al. [22] 14/9 5-fluorouracil PO 175 mg/m2 2 (0/2) Prospective
for 3 wk every 5 wk trial
No authors listed 10 Bleomycin 30 mg × 2/ wk IM 2 Prospective
[29] study
Immunotherapy
Lippman et al. [30] 32/28 Interferon alpha 2a (3 MU/d) 19 (7/12) Phase II
and retinoids 1 mg/kg/d study
Brewster et al. [14] 66 Interferon alpha 2a (3 MU × 3/wk) No improvement Randomized
and retinoids 1 mg/kg/d for 6 mo for preventing phase III
tumor recurrence study
and second skin
epidermoid
carcinoma
Combination of immunotherapy and chemotherapy
Wollina et al. [31] 4/4 Capecitabine PO (950 mg/ m2 4 (2/2) Case series
de d1 à d14) and interferon alpha
2a (3×3mo U/wk SC)
Shin et al. [33] 39/35 Retinoid acid (1 mg/kg/day orally) 12 (6/6) Phase II trial
+ interferon α (5MU/m2 × 3/wk)
+ cisplatin (20 mg/ m2/we IV)
5-FU 5-fluoruracil, 13cRA 13-cis-retinoic acid, CR complete response, PR partial response

Cisplatin and doxorubicin

& Guthrie et al. [16] treated 3 patients with SCCS with combination of
cisplatin 75 mg/m2 and doxorubicin 50 mg/m2 every 3 weeks. There
were: 1 long lasting CR, 1 PR, and 1 stabilization. The same group
has reported activity of the same combination in a prospective phase
 Therapy of Advanced Squamous Cell Carcinoma of the Skin Bejar and Maubec 305

II trial [17] including patients with advanced basal cell carcinoma

and patients with locally advanced SCCS. Among the 12 patients
with advanced CSSC, 7 responded (4 CR and 3 PR).

Cisplatin, 5-fluorouracil (5-FU) and bleomycin

& Sadek et al. [18] treated 14 patients with advanced SCCS with 1–4 cycles
of neoadjuvant combination chemotherapy (cisplatin by bolus injec-
tion, and 5-fluorouracil and bleomycin by continuous 5-day infusion).
Chemotherapy was repeated every 3–4 weeks. The response rate was
78 % (4 CR, 7 PR). Local control after adjuvant radiation and/or surgical
treatment was achieved in 7 (50 %) patients. Duration of CR lasted
more than 10 months. Major toxicities included grade 3–4 nausea and
vomiting in all patients and grade 3–4 hematological toxicities in 4
patients. Pulmonary fibrosis was observed in 1 patient.

Cisplatin and 5-fluorouracil

& A few months later, Khansur T et al. [19] reported the activity of cisplatin
and 5-FU in 7 patients with advanced locoregional or metastatic disease
who were treated every 3 weeks with cisplatin (100 mg/m2 on day 1 and
5-FU at 1 g/m2/day, day 1–day 4). Responses were observed in 6 of 7
patients (3 PR and 3 CR). The average duration of CR was 1 year. Tox-
icities included grade 1 to 2 nausea and vomiting.

Chemoradiation with cisplatin and 5-fluorouracil

& Low-dose 5-fluorouracil/cisplatin induction concurrent with radiation

(chemoradiation) has been reported to be effective for local control of
advanced squamous cell carcinoma of head and neck (SCCHN) [20].
& No trial is available for SCCS. Fujisawa et al. [21] have reported
chemoradiation with cisplatin and 5-fluorouracil in 2 patients with
locally advanced disease. A CR leaving ulceration was obtained in
both patients. In the first patient, the ulceration completely resolved
after 3 months. The second patient underwent surgical skin grafting.

Oral 5-fluorouracil

& Cartei et al. [22] in a retrospective study have investigated oral 5-fluo-
rouracil as a single agent in elderly patients (mean age of 76 years).
Manitol-coated 5-FU tablets at the daily dose of 175 mg/m2 for 3 weeks
every 5 weeks was administrated to 14 patients. Among the 9 evaluable
patients, 2 (14 %) patients presented a PR, and 3 (21 %) a minor re-
sponse; the median duration of response was 30 months. Side effects
included only grade 1 gastrointestinal toxicity.
306 Skin Cancer (WH Sharfman, Section Editor)

Other chemotherapies
Taxanes

& Although taxanes are commonly used as single agents drugs in ad-
vanced SCCS, there is only a case report of a CR in a patient treated by
cetuximab + paclitaxel for an advanced cisplatin-refractory SCCS [23].
& The efficacy of taxanes has been demonstrated in advanced SCCHN.
Combinations of taxanes with other cytotoxic drugs or with targeted
therapies have been developed.
& A phase II trial showed that weekly monotherapy of docetaxel
(30 mg/m2) was active as the first-line treatment of 38 patients with
advanced SCCHN. The response rate was 42 % [24]. A phase II
randomized trial of weekly docetaxel vs methotrexate showed higher
response rates for docetaxel but comparable survival rates [25].
& A recent meta-analysis [26] suggests the superiority of the combina-
tion of taxane with cisplatin-fluorouracil over cisplatin-fluorouracil
as induction chemotherapy in locally advanced SCCHN.
& In a phase II trial [27], 46 patients with advanced SCCHN naïve of che-
motherapy received the combination of cetuximab (400/250 mg/m2)
and weekly paclitaxel (80 mg/m2). The overall response rate was 54 %
(CR 22 %). Common grade 3/4 adverse events were acne-like rash, as-
thenia, and neutropenia.
& A phase III randomized, placebo-controlled trial of docetaxel with or
without gefitinib (250 mg/d) in advanced SCCHN showed that the
addition of gefitinib to docetaxel did not improve response rate and
survival. Diarrhea was more frequent in the gefitinib arm [28].

Bleomycin

& The administration of bleomycin alone (30 mg IM×2/week) for ad-

vanced squamous cell carcinoma (SCC) in a prospective randomized
controlled trial vs other chemotherapies (mainly cyclophosphamide or
methotrexate), in patients with SCC of head and neck but also SCCS
(n=10 including 7 perineal tumors) did not show superiority in terms
of efficacy (2 PR in patients with a tumor of the perineum). No lung
toxicity was reported. Authors concluded that bleomycin should be
administered in combination with other drugs [29].

Immunotherapy
Interferon alpha and retinoic acid

& The synergistic activity of interferon alpha and retinoids has been
reported by Lippman et al. in a phase II prospective trial including 32
patients with pretreated advanced SCCC [30]. Treatment consisted in
the combination of interferon alpha (3 MU per day) and 13-cis-
 Therapy of Advanced Squamous Cell Carcinoma of the Skin Bejar and Maubec 307

retinoic acid (13-cRA) (1 mg/kg per day) for at least 2 months.

Twenty-eight out of 32 patients were evaluable for response. The
response rate was higher in patients with locally advanced disease
(93 % [13/14]) than in patients with regional metastatic disease
(67 % [4/6]) or in patients with distant metastasis (25 % [2/8]).
& The median duration of response was 5 months. The most frequent
adverse effects included skin, eye, and lip dryness. In 18 (75 %)
patients, the treatment required a dose reduction because of fatigue
of grade 3–4.

Adjuvant interferon alpha and retinoic acid

& Brewster et al. [14] in a randomized controlled phase III trial has
assessed the combination of 13-cis-retinoic acid and interferon alpha
as adjuvant therapy after surgery and /or radiation in 66 patients with
aggressive SCCS. This combination regimen did not improve the
time to recurrence or prevent secondary cutaneous tumors. This ad-
juvant treatment cannot be recommended as adjuvant treatment for
patients with aggressive SCCS.

Oral capecitabine and interferon alpha

& Wollina et al. [31] have studied efficacy of the combination of oral
capecitabine (950 mg/m2 body surface on days 1–14) combined
with interferon alpha (3×3 MU SC 3 times a week) in a prospective
series of 4 patients with advanced SCCS. They observed 2 CR and 2
PR. Toxicities included grade 2 nausea and emesis and grade 1–2
anemia and lymphopenia. One patient died for unknown reasons.
& Currently Colevas et al. are conducting a phase II study
[NCT01823679] of capecitabine in advanced or recurrent SCCS. Pa-
tients receive capecitabine orally (PO) twice a day (BID) on days 1–
14, every 21 days [32].

Interferon alpha + retinoic acid + cisplatin

& This combination was evaluated by Shin et al. [33] in a phase II

prospective trial including 39 patients (12 with locally advanced
disease, 16 with regional metastasis, and 11 with distant metastasis).
The treatment regimen consisted of Interferon alpha, 5×106 IU/m2
by subcutaneous injections 3 times a week, 13-cis-retinoic acid 1 mg/
kg orally daily, and cisplatin 20 mg/m2 by weekly intravenous in-
jections. The response rate was higher in locally advanced disease
(67 %) than in metastatic disease (17 %). Median survival was
14.6 months. This regimen was moderately tolerated: toxicity in-
cluded mucocutaneous dryness, peripheral neuropathy, flu-like
308 Skin Cancer (WH Sharfman, Section Editor)

symptoms, and hypertriglyceridemia. Grade 3 and 4 neutropenia

occurred in 13 patients (38 %), thrombocytopenia in 13 (37 %),
and moderated to severe fatigue in 8 patients (23 %). Authors
concluded that this combined therapy was active in locally advanced
disease.
Other treatments
Hyperthermic Isolated Limb Perfusion (HILP)

& Olieman et al. [34], performed HILP in 12 patients with advanced

SCCS. Perfusion consisted of melphalan + TNF alpha + interferon
gamma, under mild hyperthermia (39 °C–40 °C), the median fol-
low-up was 20 months. After HILP, 8 (66 %) patients showed a CR.
Three patients (25 %) showed a PR and 1 patient had a stable dis-
ease. The limb salvage was achieved in 9 of 12 patients (75 %). There
was 1 toxic death in a patient with lymphedema, which is now an
exclusion criteria in the TNF-alpha-based protocols.
& HILP represents a limb saving treatment and is a valuable tool in
patients with locally advanced SCCS of the extremities without bone
involvement.

Intra-arterial infusion with methotrexate

& In 2003, Sheen et al. [35] have reported a CR in a 57-year-old male

with a SCCS of the left big toe who had refused amputation. Left
external iliac arterial catheterization and infusion with methotrexate
(50 mg) were administrated every 24 hours plus simultaneous in-
tramuscular injection of 6 mg of leucovorin every 6 hours for 8 days.
The patient had a CR that was maintained 7 years after treatment.

Drugs targeting the human epidermal growth factor receptor

& The epidermal growth factor receptor (EGFR) is a family of proteins

including EGFR, HER-2, HER-3, and HER4. Activation of EGFR ty-
rosine kinase enzyme results in autophosphorylation and activation
of signal transduction pathway leading to tumor growth.
& EGFR is strongly expressed in samples of metastatic SCCS [36] as in
head and neck cancers. In SCCHN, this overexpression is associated
to a risk of relapse and worse survival rate [37]. In contrast to lung
tumors, increased EGFR gene copy numbers in SCCHN does not
seem to be associated with improved survival [38].
& Anti-EGFR therapy consists either of the administration of mono-
clonal antibodies that competitively inhibits EGFR (cetuximab,
panitumumab) or in the administration of small molecules
targeting the intracellular domain of the receptor (gefitinib, erlo-
tinib) (Table 2).
 Therapy of Advanced Squamous Cell Carcinoma of the Skin Bejar and Maubec 309

Table 2. Details of trials targeting EGFR in cutaneous SCC

Trial Eligibility Treatment Trail N Response Disease

design rate (ITT) control rate
(ITT)
Glisson ASCO 2006 Unresectable Phase II 22 3/22 (14 %) 9/22 (41 %)
[61] trial
Lewis Clin Cancer Aggressive tumors Gefinitib Phase II 23 10/23 15/23 (63 %)
Res 2012 [62••] (≥ 2 cm or deep trial (43 %)
invasion or perineural
invasion or lymph
node involvement)
Maubec J Clin Oncol Unresectable Cetuximab Phase II 36 10/36 25/36 (69 %)
2011 [48••] trial (28 %)
Heath Int J Radiat Locally advanced Erlotinib Phase I 15 – 73 % at 1 yr
Oncol Biol Phys and recurrent trial
2013 [74] SCCS.

ITT intend to treat

Cetuximab

& Cetuximab is a chimerical monoclonal antibody that blocks the

binding of natural ligands to the EGFR, preventing EGFR dimeriza-
tion, internalization, and autophosphorylation and inhibiting sub-
sequent activation of tyrosine kinase-mediated signaling pathways.
Improved survival was shown with cetuximab in combination with
platinum-based chemotherapy and in combination with radiother-
apy in advanced SCCHN [39, 40]. Cetuximab is approved by the
FDA for the treatment of advanced SCCHN in combination with
radiation or with chemotherapy and as a single agent for patients
progressing after platinum-based therapy.
& At present, no targeted therapy is approved in SCCS. Several case
reports of responses with cetuximab have been published either in
elderly patients (n=4), or in patients with xeroderma pigmentosum
(n=1), or dystrophic epidermolysis (3 cases) [41–47].
& The efficacy of single-agent cetuximab (400 mg/m2 at week 1 and
then 250 mg/m2/week) as a first-line treatment in patients with ad-
vanced unresectable SCCS has been shown in a prospective phase II
trial [48••]. The main objective was the disease control rate at week
6. Thirty-six patients, of median age 79 years, were included. Disease
control rate at week 6 was 69 %. The response rate was 28 % at week
6. The best responses were 8 PR and 2 CR and response duration was
6.4 months. Main toxicity was grade 1–2 acne-like rash in 78 % of
patients. There were 3 related serious adverse events: 2 grade 4 in-
fusion reactions and 1 grade 3 interstitial pneumopathy.
& The most common adverse reactions of cetuximab are cutaneous adverse
reactions including acne-like rash, pruritus and nail changes, headache,
310 Skin Cancer (WH Sharfman, Section Editor)

diarrhea, and infections. There are a few reports of severe interstitial lung
toxicity. Severe infusion reactions occur in 3 % of patients.
& Interestingly, preclinical data suggest that topical application of a potent
phosphatase inhibitor menadione (Vitamin K3) could prevent skin
toxicity in mice receiving systemic EGFR inhibitors. A randomized,
double-blinded, placebo-controlled study has been initiated to evaluate
the clinical efficacy of menadione topical cream, in the treatment or
prevention of EGFR inhibitor-induced skin toxicity [49].

Adjuvant cetuximab

& O’Bryan et al. [13] have reported in a retrospective chart review of 22

patients with very high risk SCCS from to 2000 and 2012, the use of
adjuvant cetuximab in 7 patients. Only 3 of them recurred. Further
prospective randomized studies are required to determine if
cetuximab may be an active adjuvant therapy for high risk SCCS.

Determinants of response to cetuximab

& Acne-like rash has been reported as a clinical marker of response.

There was a survival advantage or a prolonged progression free sur-
vival in patients who developed a rash [48••, 49–51].
& Tumor EGFR expression levels have not been associated with treat-
ment efficacy [50, 52, 53].
& Studies in patients with metastatic colorectal cancer treated with
cetuximab have shown that Fc gamma RIIa and Fc gamma RIIIa
polymorphisms are independently associated with clinical outcome
[54]. In vitro data from SCCHN have shown that extent of lysis of
cells was influenced by Fc gamma receptor polymorphism [55].
Available clinical data in SCCS could not confirm the prognostic
value of these polymorphisms.
& Tumor EGFR copy number is not a predictive biomarker for the ef-
ficacy of cetuximab plus chemotherapy as first-line therapy for pa-
tients with SCCHN [56].
& Other molecular determinants of response to cetuximab, as cytoplasmic
expression of PTEN and p53 mutations, have been identified in patients
with metastatic colorectal cancers without KRAS mutation. The value of
these markers has not been confirmed in SCCHN or SCCS [57].
& The identification of predictive biomarkers for efficacy is now a
crucial issue.

Gefitinib

& Gefitinib is an orally active agent that inhibits the tyrosine kinase ac-
tivity of EGFR. It has been approved by FDA for patients with non-small
 Therapy of Advanced Squamous Cell Carcinoma of the Skin Bejar and Maubec 311

cell lung cancer. In head and neck tumors, the response rate of gefitinib
as single-agent (500 mg/d) has been evaluated to 10.6 % in a phase II
study [58]. Gefitinib compared with methotrexate did not improved
survival in a phase III study [59]. The most common adverse events
reported were diarrhea, rash, acne, dry skin, nausea, and vomiting.
& Regarding SCCS, Baltaci et al. [60] reported 1 minor response with
gefitinib (500 mg daily) in an 82-year-old man with an advanced
locally infiltrating tumor of the face.
& Glisson et al. [61] have evaluated gefitinib (250 mg/day) in a pro-
spective phase II trial enrolling 22 patients with advanced or recur-
rent SCCS. Twenty patients were evaluable. Disease control rate was
45 % (9/20 evaluable patients). There were 3 (14 %) responses.
Results of this trial were not published.
& Lewis et al. [62••] have conducted a prospective phase II study to
evaluate the efficacy of gefitinib as neoadjuvant therapy for patients
with aggressive SCCS (tumors of 2 cm or more, tumors with deep in-
vasion or perineural invasion, or tumors with lymph nodes involve-
ment. Gefitinib (250 mg/day) was administrated prior to surgery or
radiotherapy. Two-year disease-specific survival and progression-free
survival rates were 72.1 %, and 63.6 %, respectively. The response rate
was 45.5 % (18.2 % of CR and 27,3 % of PR). Common grade 1 to 2
toxicities were diarrhea, fatigue, acneiform rash, anemia, and nausea.
Four patients presented grade 3 toxicities including fatigue, elevation of
AST, and ALT. The authors suggested that gefitinib might be further
explored in the treatment of aggressive SCCS.

Determinant of response to gefitinib

& Skin toxicity was found to be a predictor of response, progression,

and survival.
& There is no association between EGFR receptor expression and re-
sponse to gefitinib.
& Gefitinib has shown a high efficacy in patients with non-small cell
lung carcinoma and specific mutations of EGFR [63, 64]. However,
these mutations are rare in SCCHN and in SCCS [65, 66]. One in
vitro study in SCCHN cell lines suggests that EGFR gene mutation,
amplification, and genomic gain correlated strongly with gefitinib
sensitivity [67].
& However, in humans SCCHN and SCCS, correlations between mu-
tation or gene gain, response, and survival rate have not been dem-
onstrated. Because of the limited number of patients and low
incidence of genetic aberrations in EGFR, additional studies are
warranted.
& EGFRvIII mutation, present in about 40 % of SCCHN, was found to
be a biomarker of better disease control in 1 study [68].
& Insulin-like growth factor receptor 1 (IGF1R) activation is a suggested
312 Skin Cancer (WH Sharfman, Section Editor)

mechanism of resistance to EGFR tyrosine kinase inhibitors. In a

phase II study evaluating postoperative irradiation associated to cis-
platin + gefitinib in patients with SCCHN, elevated expression of
IGF1R was significantly associated with shorter DFS [69]. IGF1R ac-
tivation partially reverses the cell cycle arrest caused by gefitinib in
SCCHN cells. This may contribute to the ability of the IGF1R to
rescue tumoral cells from EGFR inhibitors [70]. Combination or co-
targeting of IGFR and EGFR might be of interest.
& In conclusion, in contrast to non-small cell lung carcinoma, few
predictive factors of response have been identified in SCCHN or
SCCS. There is a medical need to identify which patients with SCCS
are most likely to benefit from therapy with EGFR inhibitors.

Erlotinib

& Erlotinib is another orally active agent that inhibits the tyrosine ki-
nase activity of EGFR. It is approved for the treatment of non-small
cell lung cancer and advanced pancreatic tumors. The most common
adverse reactions with erlotinib are rash, diarrhea, anorexia, fatigue,
dyspnea, cough, nausea, and vomiting.
& In 2007 Read et al. [71] reported 3 patients with SCCS, for whom
erlotinib treatment (150 mg daily) produced clinical benefit. One
patient with lung metastases previously treated with acitretin and
interferon achieved a PR of lung metastases. One achieved a CR after
1 month of treatment, with disease recurrence when erlotinib was
discontinued. The last patient achieved a PR after 3 months [72].
Authors concluded that erlotinib provided excellent palliation for
these patients who had failed to respond to other therapies.
& Engelhardt et al. [73] reported 1 patient with a SCCS with
unresectable regional disease, strongly expressing EGFR. After 1 week
of treatments with erlotinib, the patient’s pain markedly improved.
Disease remained stable for 4 months before progression suggesting
that assessment of erlotinib’s single-agent activity may be warranted.
& A phase I study [74] has evaluated the toxicity profile of erlotinib
combined with radiotherapy for advanced and recurrent SCCS. Fifteen
patients were enrolled, 7 with local disease, and 8 with regional disease;
87 % of primary lesions were classified as T4. The pre-treatment regimen
consisted of erlotinib (150 mg daily for 2 weeks) prior to surgical re-
section. Adjuvant combination of erlotinib and radiotherapy followed
surgical resection for 6 weeks. Toxicity included grade 2–3 dermatitis in
all patients (100 %), mucositis in 13 patients (87 %), esophagitis in 11
patients (40 %), nausea and vomiting and dehydratation in 10 patients
(47 %). The incidence of grade 3 adverse events was higher than usually
observed with radiotherapy. One patient had a myocardial infarction.
In 5 (33 %) patients dose modifications were needed. The mean follow-
up time was 21.7 months and median time to recurrence was
 Therapy of Advanced Squamous Cell Carcinoma of the Skin Bejar and Maubec 313

10.5 months. The 2-year recurrence rate and overall survival were 27 %
and 65 %. In this trial erlotinib seemed to potentiate radiation related
cutaneous toxicity.

Neoajuvant erlotinib

& Neoajuvant erlotinib is another area under investigation. Currently,

the MD Anderson cancer Center is conducting a phase II trial
[NCT01198028] of erlotinib prior to surgery or radiation for SCCS
that is either locally advanced or recurrent with no evidence of dis-
tant metastases [75].
Interventional procedures
Radiotherapy

& SCCS is a radiosensitive tumor. Indeed, in patients with resectable

lymph node metastasis, survival is significantly improved with ad-
juvant radiotherapy [76].
& Radiotherapy alone is an option of treatment of locally or regionally
advanced disease especially in elderly patients with comorbidities when
other treatments seem to be difficult to administrate. Although re-
sponses to radiotherapy have been reported in case reports or in het-
erogeneous series including often both T4 basal cell carcinoma and
SCCS [77–81], patients with advanced disease are unlikely to reach
durable locoregional control. SCCS have a much poorer outcome than
basal cell carcinoma and can recur quickly after radiotherapy [81]. The
addition of chemotherapy to radiotherapy in patients with locally or
regionally advanced CSSC is experimental and may be considered only
in suitable good performance patients [17].
& Radiation therapy can cause both acute and chronic side effects. The
acute side effects occur during treatment and include reversible der-
matitis or mucositis. Late side effects include skin atrophy with loss
of hair and sweat and sebaceous secretions, discoloration, telangi-
ectasia, hypodermic sclerosis, and skin carcinomas.
& Radiation therapy must be avoided in patients with condition that
predispose them to radiation-induced cancers, such as basal cell
nevus syndrome and xeroderma pigmentosum.

Considerations for immunocompromised patients

Interest of mTOR inhibitors

& SCCSs being evolutive in immunocompromised patients, they require

rapid treatment. Specific treatment is generally the same as in immuno-
competent patients. In organ transplant recipients, reducing immuno-
suppression should be considered. The only class of immunosuppressants
with proven antitumoral efficacy is mTOR inhibitors.
314 Skin Cancer (WH Sharfman, Section Editor)

& The American Transplant Registry shows a lower incidence of solid

tumors in patients treated with mTOR inhibitors compared with
patients receiving a calcineurin inhibitor (0.5 % vs 1.5 %) [82].
Switching from calcineurin inhibitors to sirolimus among kidney-
transplant recipients with previous SCCS prevents the occurrence of
new SCCS [83–85]. A phase II [NCT01764607] randomized study to
evaluate the effectiveness of sirolimus in treating SCCS in kidney
transplant patients is ongoing [86].
& The administration of mTOR inhibitors remains limited because of
poor tolerance. Indeed, 25 %–40 % of patients, required discontin-
uation of treatments because of adverse events such a hyperlipid-
emia, glucose intolerance, interstitial pneumonia, inflammatory
acneiform eruptions, lymphedema, and mucositis [87].
Specific emerging therapies
Potential new therapeutic targets

& There are several new candidate treatment targets for unresectable
SCCS.
& Except p53 mutations, few recurrent genetic aberrations have been
identified in SCCS and driver somatic mutations are lacking. It has
been recently shown, using an exome sequencing strategy, that
NOTCH1 or NOTCH2 inactivating mutations represent a frequent
event in SCCS tumors [88••]. NOTCH signaling is negatively regu-
lated by the EGFR pathway [89]. Mice carrying a mesenchymal-spe-
cific deletion of CSL/RBP-Jκ, a key NOTCH effector, exhibit
spontaneous multifocal keratinocyte tumors [90].
& ALK1 is a new promising target for antiangiogenic therapy of cancer
[91]. In SCCHN, dalantercept, that prevents activation of ALK, has
shown an activity in a phase 1 study [92]. A phase II trial
[NCT01458392] with dalantercept is ongoing in SCCHN [93].
& Increased expression of matrix metallopeptidase 7 (MMP7) in inva-
sive SCCS has been recently shown by complementary DNA micro-
array analysis [94••]. MMP7 enhances proliferation, migration, and
invasion of cancer cells. Interestingly, blocking of MMP7 delayed the
migration of tumoral cells.

New combinations with EGFR inhibitors

& Moreover, new therapeutic approaches with EGFR inhibitors, mainly

combinations, are currently under evaluation in SCCHN and might
represent valuable therapeutic approaches for advanced SCCS. These
combinations include: EGFR and VEGFR inhibitors, combination of
EGFR inhibitors (antibody and small molecules), or EGFR and IGFR
inhibitors, combination of EGFR inhibitors and chemotherapy or
radiotherapy, EGFR inhibitors and immunomodulators as Toll like
 Therapy of Advanced Squamous Cell Carcinoma of the Skin Bejar and Maubec 315

receptors, EGFR and PI3K-mTOR inhibitors. The PI3K-AKT pathway

is downstream of EGFR and is emerging as potentially one of the
most important pathways in SCCHN. A phase 1 study of cetuximab
and everolimus in solid cancers suggests that these drugs can be
safely administered, and are associated with prolonged disease con-
trol [95•].
Conclusions
There is no standard approach in locally advanced or metastatic squa-
mous cell carcinoma of the skin. Outside of a clinical trial, currently
cisplatin-based chemotherapies remain the first choice therapy but their
administration can be limited by cisplatin toxicity. Carboplatin-combi-
nation therapy is better tolerated and can be administrated as an alter-
native in older patients with multiple comorbidities. Hyperthermic
isolated limb perfusion has to be considered as a limb saving treatment
in patients with unresectable disease located on extremities. Taxanes or
methotrexate can be proposed in the second line setting. Combined bi-
ological therapy with 13-cis-retinoic acid and interferon-alpha-2a repre-
sents a second-line treatment option as well, although fatigue is a major
limiting side effect in elderly patients. An initial work up for a global
assessment is needed in order to adapt the choice in elderly patients.
As SCCSs are often evolutive in immunocompromised patients, they re-
quire rapid treatment. Specific treatment is generally the same as in immuno-
competent patients. Moreover, in organ transplant recipients, the change
from calcineurin inhibitors to sirolimus or reduce immunosuppression ther-
apy should be considered.
Blockade of EGFR signaling achieves a therapeutic activity. However, there is
a need for phase III trials to evaluate the optimal administration strategy.
The recent identification of molecular alterations in squamous cell
carcinoma of the skin and in head and neck tumors might lead to the de-
velopment of new targeted therapies.

Acknowledgments
The authors thank Prof. MF. Avril for her helpful comments and Renato Torres for support in the prepa-
ration of this manuscript.

Compliance with Ethics Guidelines

Conflict of Interest
Claudia Bejar and Eve Maubec declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.
316 Skin Cancer (WH Sharfman, Section Editor)
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