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The combination of immune checkpoint inhibitors and definitive radiotherapy is investigated for the multimodal treatment of cisplatin non-eligible locally advanced head and neck cancers (HNC). In the case of recurrent and metastatic HNC, immunotherapy has shown benefit over the EXTREME protocol, being already considered the standard treatment. One of the biggest challenges of multimodal treatment is to establish the optimal therapy sequence so that the synergistic effect is maximal. Thus, superior results were obtained for the administration of anti-CTLA4 immunotherapy followed by hypofractionated radiotherapy, but the anti-PD-L1 therapy demonstrates the maximum potential of radio-sensitization of the tumor in case of concurrent administration. The synergistic effect of radiotherapy-immunotherapy (RT-IT) has been demonstrated in clinical practice, with an overall response rate of about 18% for HNC. Given the demonstrated potential of radiotherapy to activate the immune system through already known mechanisms, it is necessary to identify biomarkers that direct the "nonresponders" of immunotherapy towards a synergistic RT-IT stimulation strategy. Stimulation of the immune system by irradiation can convert "nonresponder" to "responder". With the development of modern techniques, re-irradiation is becoming an increasingly common option for patients who have previously been treated with higher doses of radiation. In this context, radiotherapy in combination with immunotherapy, both in the advanced local stage and in recurrent/metastatic of HNC radiotherapy, could evolve from the "first level" of knowledge (i.e., ballistic precision, dose conformity and homogeneity) to "level two" of "biological dose painting" (in which the concept of tumor heterogeneity and radio-resistance supports the need for doses escalation based on biological criteria), and finally to the "third level" ofthe new concept of "immunological dose painting". The peculiarity of this concept is that the radiotherapy target volumes and tumoricidal dose can be completely reevaluated, taking into account the immune-modulatory effect of irradiation. In this case, the tumor target volume can include even the tumor microenvironment or a partial volume of the primary tumor or metastasis, not all the gross and microscopic disease. Tumoricidal biologically equivalent dose (BED) may be completely different from the currently estimated values, radiotherapy treating the tumor in this case indirectly by boosting the immune response. Thus, the clinical target volume (CTV) can be replaced with a new immunological-clinical target volume (ICTV) for patients who benefit from the RT-IT association (Image 1).

Synergies Radiotherapy-Immunotherapy in Head and Neck Cancers. A New Concept for Radiotherapy Target Volumes—“Immunological Dose Painting”