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).

Locally advanced head and neck cancer is a unique challenge for cancer management in the Covid-19 situation. The negative consequences of delaying radio-chemotherapy treatment make it necessary to prioritize these patients, the continuation of radiotherapy being indicated even if SARS-CoV-2 infection is confirmed in the case of patients with moderate and mild symptoms. For an early scenario, the standard chemo-radiotherapy using simultaneous integrated boost (SIB) technique is the preferred option, because it reduces the overall treatment time. For a late scenario with limited resources, hypo-fractionated treatment, with possible omission of chemotherapy for elderly patients and for those who have comorbidities, is recommended. Concurrent chemotherapy is controversial for dose values >2.4 Gy per fraction. The implementation of hypo-fractionated regimens should be based on a careful assessment of dose-volume constraints for organs at risks (OARs), using recommendations from clinical trials or dose conversion based on the linear-quadratic (LQ) model. Induction chemotherapy is not considered the optimal solution in this situation because of the risk of immunosuppression even though in selected groups of patients TPF regimen may bring benefits. Although the MACH-NC meta-analysis of chemotherapy in head and neck cancers did not demonstrate the superiority of induction chemotherapy over concurrent chemoradiotherapy, an induction regimen could be considered for cases with an increased risk of metastasis even in the case of a possible Covid-19 pandemic scenario.

Xerostomia is commonly associated with the radio-chemotherapy treatment of the head and neck cancers. The risk increases with increasing doses received by the parotid. Severe xerostomia (defined as long-term salivary function of < 25% of baseline) may be avoided if at least one parotid gland receives less than 20 Gy. The combined treatment with cisplatin regarded as bringing a significant benefit in survival with concurrent radiotherapy is associated with increased risk of late toxicity. Intensity-modulated radiotherapy (IMRT) is considered the radio-therapeutic standard in the management of head and neck cancer. Purpose: to evaluate the possibility of modern techniques to reduce radiation doses to parotid glands compared to conventional 3D-CRT radiotherapy even if the parotid glands are not delineated as organs at risk (OAR) and dosimetric constraints are not applied. Methods: For 10 locally advanced nasopharyngeal cancer cases treated by radiotherapy with curative intent using 3D-CRT technique, alternative IMRT and VMAT plans were proposed without applying dosimetric constraints for parotid glands. Results: IMRT and VMAT techniques reduce the maximum dose (Dmax) and the mean dose (Dmean) for both parotid glands compared to the 3D-CRT technique. The treatment plans were comparatively analyzed in terms of doses received by both parotid glands. Conclusions: Modern radiotherapy techniques implementation can reduce the dose received by the parotids even in the absence of contouring them as organs at risk, reducing xerostomia and ensuring a better quality of life for the nasopharynx cancer radio-treated patients.

No abstract

Diabetes mellitus is often associated with a risk of developing some types of cancer. The association between head and neck cancers and diabetes as well as prognosis and treatment tolerance remains a controversy. Acute toxicities associated with treatment may be amplifi ed by the presence of comorbidities, including hypertension, diabetes and collagen diseases. Another factor implicated in the treatment tolerance is also the limitation by the presence of hyperglycemia of the corticosteroids dose used for the control of pain and edema associated with chemo-irradiation and for the treatment of thrombocytopenia. The purpose of the study was to evaluate the involvement of diabetes mellitus in the toxicities associated with chemo-radiotherapy treatment in multimodal treated patients for advanced local head and neck cancers. For patients with locally advanced non-metastatic head and neck treated with multimodal (chemo-radiotherapy) acute toxicities (radio-dermitis, radio-mucositis, dysphagia) was analyzed comparatively in patients who associate or not cancer with diabetes. It was also compared if the diagnostic of diabetes influenced the intensity of chemotherapy. Identifying the predictive value of diabetes mellitus for the severity of toxicities in multimodal curative treatment for head and neck cancers can lead to limitation of radiation dose to some radiosensitive anatomical structures in the context of the modern IMRT and VMAT irradiation techniques implementation in clinical practice.