Immunotherapy, the modern oncological treatment with immune checkpoint inhibitors (ICIs), has been part of the clinical practice for malignant melanoma for more than a decade. Anti-cytotoxic T-lymphocyte antigen 4 (CTLA4), anti-programmed cell death Protein 1 (PD-1), or anti programmed death-ligand 1 (PD-L1) agents are currently part of the therapeutic arsenal of metastatic or relapsed disease in numerous cancers; more recently, they have also been evaluated and validated as consolidation therapy in the advanced local stage. The combination with radiotherapy, a treatment historically considered loco-regional, changes the paradigm, offering—via synergistic effects—the potential to increase immune-mediated tumor destruction. However, the fragile balance between the tumoricidal effects through immune mechanisms and the immunosuppression induced by radiotherapy means that, in the absence of ICI, the immune-mediated potentiation effect of radiotherapy at a distance from the site of administration is rare. Through analysis of the preclinical and clinical data, especially the evidence from the PACIFIC clinical trial, we can consider that hypofractionated irradiation and reduction of the irradiated volume, in order to protect the immune-infiltrated tumor microenvironment, performed concurrently with the immunotherapy or a maximum of 2 weeks before the start of ICI treatment, could bring maximum benefits. In addition, avoiding radiation-induced lymphopenia (RILD) by protecting some anatomical lymphoid structures or large blood vessels, as well as the use of irradiation of partial tumor volumes, even in plurimetastatic disease, for the conversion of a "cold" immunological tumor into a “hot” immunological tumor are modern concepts of radiotherapy in the era of immunotherapy. Low-dose radiotherapy could also be proposed in plurimetastatic cases, the effect being different (modeling of the TME) from that of high doses per fraction irradiation (cell death with release of antigens that facilitates immune-mediated cell death).
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Background and purposeThe aim of this paper is to compare neural induced changes in three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) for nasopharyngeal cancers.Materials and methodsRadiotherapy plans for 10 patients with nasopharyngeal cancer stages III and IV were prospectively developed for 3D-CRT, IMRT and VMAT using Varian Eclipse planning system. The same radiation therapist carried out all planning and the same clinical dosimetric constraints were used. Normal tissue complication probabilities were calculated.ResultsThe mean planning target volume’s (PTVs) conformity index (CI) for 3D-CRT was 1·424, for IMRT 1·1, and for VMAT 1·081. The PTV homogeneity (HI) index was 0·204 for 3D-CRT, 0·124 for IMRT and 0·153 for VMAT. Normal tissue complication probabilities gave complex results for 3D-CRT, IMRT and VMAT and are analysed in detail in this paper. The mean monitor units were 95 (range 9–180) for 3D-CRT; 165 (range 52–277) for IMRT; and 331 (range 167–494) for VMAT (p<0·05).ConclusionsVMAT is associated with similar dosimetric advantages as IMRT over 3D-CRT for nasopharyngeal cancer. VMAT is associated with faster delivery times and greater number of mean monitor units than IMRT. Brain radionecrosis severity and risk, in the past, have been underestimated. By improving the life expectancy of patients with nasopharyngeal cancer to ensure maintenance of the neural structures, recommended dose limits should be considered as a first degree priority (as the spinal cord, brainstem, etc.) when IMRT and VMAT plans are implemented.
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