## 4 Discussions
Conforming to National Comprehensive Cancer Network (NCCN) [4], adjuvant radiotherapy may be applied in selected cases: radiotherapy regimens are not well established but include: Total Dose (TD) = 60-66 Gy in 30-33 fractions over 6-7 weeks, TD = 48 Gy in 20 fractions over 4 weeks and TD = 30 Gy/5 fractions over 2 weeks. Definitive or palliative radiotherapy for regional metastases can also be given in TD = 50 Gy/20 fractions/4 weeks, TD = 30 Gy in 10 fractions/2 weeks, TD = 30 Gy in 5 fractions/2 weeks, TD = 20 Gy in 5 fractions/1 week and TD = 8 Gy in 1 fraction/1 day [4]. Hypofractionation appears to be equivalent in effectiveness to conventional fractionation with mild toxicity. The combination of radiotherapy plus immunotherapy offers a chance to increase the immunostimulatory potential of radiation and appears to be a secure treatment, which is also sustained by strong biological reasons. Valid data confirm that radiotherapy is more usually used for metastatic rather than non-metastatic disease. Such a combination shows encouraging results in terms of survival results; however, further studies are needed to confirm such evidence [30]. It has been a long time since radiation was considered to determine immunogenic modulation; cell death, through the induction of dendritic cells; cell adhesion molecules; death receptors and tumor-associated antigens, as well as DNA strand breaks, apoptosis, and necrosis. In fact, radiation instead transforms the tumor into an individualized vaccine [29]. Due to the immune priming effect of radiotherapy, there is a great and complex biological motive and a strong proof for synergy in combination with immune checkpoint inhibitors, which these days are first-line therapy in patients with recurrent or metastatic melanoma. Specialist information indicates that the bystander effect is induced by radiotherapy. This means the increasing therapeutic response of tumors outside of irradiated areas, in this way, also increases the possibility of tumor formation at distant sites [31]. Interaction between radiotherapy and immunotherapy was analyzed in retrospective trials and the results evidenced the abscopal response based on the activation of IFN-1 via cGAS and STING lane in the radio-treated neoplastic cells. In a patient with a progressive disease during immunotherapy, radiotherapy was given for local control and very good systemic results were obtained [32]. There is a considerable potential to improve local control and abscopal effects by concurrent radiotherapy plus immunotherapy or radiotherapy plus hyperthermia or the combination of all three modalities, indicated as the next important trial in this refractory disease [30; 31; 32]. It is well known that there is a lack of data and clinical studies regarding combined radiotherapy with immunotherapy, yet recent studies show that some appropriate patients can perform concurrent neoadjuvant radiotherapy and immunotherapy to reduce the toxicity of a planned surgical resection--which, historically, has a low chance for a systemic cure [9, 31, 32, 33, 34, 35] and the efficacy of ipilimumab used concurrently with radiation in patients with metastatic melanoma highlights the potential synergy of this combination [33, 34, 35, 36, 37]. [PERSON] et al. [9] presented a study with a few patients with vaginal and cervix melanoma. All four patients received ipilimumab with concurrent EBRT and three patients with persistent disease after combined treatment underwent less extensive surgical procedures. The radiation therapies doses varied between TD = 30 Gy/5 fractions and dose/fraction (d/fr) = 600 cGy with TD = 6020 cGy/28 fr, d/fr = 215 cGy. Vaginectomy was performed during a period of between 33-97 days post-radiation therapy. All the information from clinic work and from the literature sustain the idea that palliative radiotherapy for secondary brain malignancy, also functioned for extracranial metastatic sites. In cases with increased risk of local and nodal relapse, the adjuvant radiotherapy is also recommended [29].