Page 83 - Read Online

Page 2 of 9 Lo Re et al. J Cancer Metastasis Treat 2020;6:17 I http://dx.doi.org/10.20517/2394-4722.2020.11

INTRODUCTION
In 2018, cutaneous squamous cell carcinoma (cSCC) was reported to be the 5th most common type of
[1]
cancer with 5.8% and 0.7% rates of incidence and mortality respectively . It shows racial and gender
differences with greater incidence in white than black subjects and in men than women. The incidence
[2]
increases with age, with an average age around 60 years . Tumor aggressiveness is associated with
histological type. In fact, well-differentiated histologic subtypes such as keratoacanthoma and verrucous
carcinoma are associated with low metastatic potential and do not seem related to human papillomavirus
[3]
(HPV) infection . On the contrary, there are histological variants characterized by greater tumor
[4]
aggressiveness, metastatic potential and poor prognosis and are represented by desmoplastic and
[5]
adenosquamous cSCC. However, the absence of negative features such as epithelial dysplasia and stromal
invasion in verrucous carcinoma can determine differential diagnostic difficulties with other benign
[7]
[6]
entities . The most important prognostic factors are tumor diameter > 2.0 cm , tumor depth (< 2 mm
[8]
[9]
vs. > 2 mm) and perineural involvement , which are highly associated with local recurrence, nodal
metastases and disease-specific death. Sun exposure, age, fair skin, and immunosuppression are the main
[10]
[11]
risk factors. Immunosuppression, associated with organ transplantation or other lymphoproliferative
[12]
or solid tumors , negatively affects the behavior of the disease and probably also the responsiveness
to treatments. Surgery and radiotherapy are the main modalities of treatment once the diagnosis has
been made or after loco-regional recurrence with good results in terms of relapse-free survival, which
[13]
is influenced by the state of immunosurveillance . The treatment of metastatic disease up to now has
[15]
[14]
been by chemotherapy [14-19] , and it should be noted that cisplatin (DDP) and fluorouracil (FU) are the
most active chemotherapeutic agents. Regarding anti-epidermal growth factor receptor (EGFR) therapy,
[20]
[14]
cetuximab seems to be more active than panitumumab with complete response (CR) of 68% and
12.5%, overall response rate (ORR) of 78% and 31% and progression-free survival of 25 and 8 months,
respectively.
In comparison, ORR of patients treated with DDP is 45% comprising 22% CR with a median disease-free
[14]
survival of 14.6 months . One of the mechanisms of DDP resistance could be linked to MiR-3619-5p
[19]
downregulation, responsible for cell proliferation . To overcome drug resistance, considering the
synergistic action between different types of chemotherapeutic agents such as DDP and fluoropyrimidines
[21]
[17]
[16]
[22]
[e.g., FU or capecitabine (Cape)] , DDP and taxanes , and taxanes and fluoropyrimidines , there
is a rationale for a combination of these drugs. Recently, we have witnessed an explosion in research on
new immunotherapeutic agents that have come into clinical practice both in solid and hematological
tumors. In 2018, the US FDA approved cemiplimab-rwlc, a human anti-programmed death 1 (PD-1)
monoclonal antibody, which blocks the interaction of PD-1 with programmed death ligand-1 (PD-L1)
and represents the first and sole treatment specifically approved and available for advanced cSCC. The
approval of cemiplimab-rwlc was based on a combined analysis of data from a phase II trial (EMPOWER-
CSCC-1 Study 1540) and a phase I trial with two advanced cSCC expansion cohorts (Study 1423). In
108 patients with metastatic or locally advanced disease, there was a 47.2% objective response, and G
[14]
≥ 3 SAE was observed in 29% of cases . Regarding other anti-PD1 agents such as nivolumab [24-28] and
pembrolizumab [29-35] , there are positive reports with small series [Table 1].

Regarding the negative effect of immunosuppressive cells such as regulatory T lymphocytes (Tregs)
and myelo-derived suppressor cells (MDSCs) on resistance to treatment with clinically unfavorable
outcome and in light of the possible inhibitory interference of cyclophoshamide (Cyc) and FU on this cell
population, the aim of the study was to evaluate an innovative chemo-immunotherapy modality including
interleukin-2 (IL-2) in the treatment of cSCC.

Our patient with low performance status had advanced cSCC originating from the right breast and
concomitant non-Hodgkin lymphoma (NHL), and was therefore not amenable to combination