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Page 8 of 14 Woods et al. J Cancer Metastasis Treat 2022;8:22 https://dx.doi.org/10.20517/2394-4722.2022.28

worse outcomes in cutaneous SCC, but this feature in cutaneous SCC is associated with higher nodal
[50]
burden and may be different from the tumor biology associated with mucosal disease . Thus, further
research is needed to determine if there is any role for concurrent chemotherapy with radiation in the
adjuvant setting for NMSC. Recent studies evaluating the use of radiotherapy with immunotherapy, such as
cemiplimab or pembrolizumab, in locally advanced unresectable cutaneous SCC have shown promising
results and further research is needed to clarify the role of concurrent radiation with immunotherapy [112-114] .

Separately, MCC is a highly radiosensitive tumor. Treatment of the neck includes either elective nodal
radiation [115,116] , or sentinel node biopsy followed by adjuvant radiation or lymph node dissection if positive,
or by observation alone if negative [116,117] . Elective nodal radiation may be avoided in T1 cases with negative
sentinel nodes [118,119] . Conventionally fractionated radiation with a dose of 50 Gy in 25 fractions is used in the
[121]
[120]
elective setting , however, single fraction treatment with 8 Gy has also been proposed . For lymph node
metastases, adjuvant radiation is advocated to improve locoregional control, but has not been shown to
[122]
improve overall survival . Higher radiation doses up to 60 Gy have been suggested for definitive treatment
of unresectable diseases, especially for treating bulky diseases .
[123]
While most adnexal tumors are resistant to radiation, the role of radiation is not clear due to heterogeneity
of tumors. Adjuvant radiotherapy may be considered in patients with microcystic adnexal carcinoma, as
well as certain others such as syringocystadenocarcinoma papilliferum and pilomatrix carcinoma [124,125] .

SYSTEMIC THERAPY
Immunotherapy has been revolutionary in the management of melanoma, but the role of systemic therapy
in NMSC is not clear. Hedgehog pathway inhibitors, and more recently immune checkpoint inhibitors, have
[126]
been approved for use in metastatic BCC or advanced BCC not amenable to surgery or radiation . For
MCC, avelumab, an anti-programmed death-ligand 1 (PD-L1) inhibitor, has been recommended as first-
line treatment for metastatic MCC due to results showing median overall survival of 20.3 months with its
[127]
use in a phase two study . A recent study, in which two-thirds of MCC patients had locoregional disease
at presentation, demonstrated that treatment with neoadjuvant nivolumab resulted in a pathological
complete response in 47.2% .
[128]
For advanced unresectable or metastatic SCC, traditional chemotherapy and/or epidermal growth factor
receptor inhibitors have been used with modest success, with median overall survival of
15.3-16.2 months . Phase two trial data on the use of cemiplimab in metastatic and locally advanced
[129]
[130]
cutaneous SCC have shown complete or partial response rates of 47% , and so cemiplimab is now the
[5]
mainstay in most clinical regimens . In the phase two study by Migden et al., an intravenous dose of
cemiplimab (3 mg per kilogram of body weight) was administered every 2 weeks and patients were assessed
for a response every 8 weeks . In this study, complete or partial response was observed in 49% of patients
[130]
with distant metastasis and 43% of patients with regional metastasis . In another phase two study where
[130]
patients received pembrolizumab, 200 mg intravenously every three weeks, complete and partial response
rates were 17% and 33%, respectively, for locally advanced unresectable disease, while complete and partial
[131]
response rates were 11% and 25%, respectively, for recurrent or metastatic disease . In a separate phase
two study of pembrolizumab, higher response rates were seen in patients with PD-L1-positive disease (55%)
compared to PD-L1-negative disease (17%) . Importantly, responses seem to be durable with manageable
[132]
safety in these studies.

Taxanes are the primary treatment in advanced unresectable angiosarcoma, while research on vascular
endothelial growth factor inhibitors, checkpoint inhibitors, and eribulin mesylate has not shown significant