Advanced or Metastatic Cutaneous Squamous Cell Carcinoma: The Current and Future Role of Radiation Therapy in the Era of Immunotherapy

SIMPLE SUMMARY: Nodal and distant metastases of cutaneous squamous cell carcinomas are very rare and lead to dismal prognoses. Immunotherapy is approved only for cutaneous squamous cell carcinoma patients not amenable to surgery or curative radiation therapy. Radiation therapy has a clear role as an adjuvant treatment for locally advanced disease. Radiation therapy may also have an important role in inoperable and metastatic disease. Oligometastatic disease is a condition that needs to be defined for this carcinoma. This review aims to offer to the readers a comprehensive overview of studies about the role of radiotherapy in the management of advanced or metastatic cutaneous squamous cell carcinomas, also assuming possible further developments in the light of the recent discoveries about tumor biology. The present paper has the merit of re-focusing great attention on the efficacy and cost-effectiveness of radiotherapy in these not yet properly explored scenarios. ABSTRACT: Radiation therapy (RT) is an effective therapeutic option for small localized cutaneous squamous cell carcinoma (cSCC) among patients who are not eligible for or refuse surgery. RT also has a defined role as an adjuvant treatment in cases of adverse features that predispose to tumor recurrence after local excision. Since the development of cSCC is often a late consequence of chronic sun exposure, its occurrence is more common among elderly patients whose comorbidities may contraindicate surgical procedures. These could be impeded not only by frail medical conditions but also by technical issues. Indeed, an aggressive locoregional behavior of cSCC may culminate in unresectability due to widespread invasion of neighboring tissues. Moreover, cSCC could develop distant metastases. Both locally advanced and metastatic cSCCs carry a poor prognosis. In these scenarios, recent discoveries of tumor molecular targets are promoting the use of promising systemic therapies, especially immunotherapy, over RT. However, the results from using immunotherapy and, even more so, of chemotherapy are still not optimal. By contrast, advances in radiation delivery equipment can safely treat even large and complex-shaped cSCC targets in challenging body sites. In addition, RT could also have a role in metastatic cSCC settings by enhancing the effectiveness of concomitant immunotherapy. The aim of this review is to summarize and comment on the body of literature about the use of radiotherapy for operable and inoperable locally advanced cSCCs and for metastatic ones in an attempt to define its current and future role.