Microenvironmental conditions control the entrance and thriving of cytotoxic lymphocytes in tumors, allowing or preventing immune-mediated cancer cell death. We investigated the role of tumor-infiltrating lymphocyte (TIL) density in the outcome of radiotherapy in a series of squamous cell head–neck tumors (HNSCC). Moreover, we assessed the link between markers of hypoxia and TIL density. One-hundred twenty-one patients with HNSCC treated prospectively with radical radiotherapy/chemo-radiotherapy were analyzed. The assessment of TIL density was performed on hematoxylin and eosin biopsy sections before radiotherapy. TIL density ranged from 0.8 to 150 lymphocytes per ×40 optical field (median 27.5). Using the median value, patients were grouped into two categories of low and high TIL density. Early T-stage tumors had a significantly higher TIL density (p < 0.003), but we found no association with N-stage. Overexpression of HIF1α, HIF2α, and CA9 was significantly linked with poor infiltration by TILs (p < 0.03). A significant association of high TIL density with better disease-specific overall survival and improved locoregional relapse-free survival was noted (p = 0.008 and 0.02, respectively), which was also confirmed in multivariate analysis. It is concluded that HNSCC phenotypes that allow for the intratumoral accumulation of lymphocytes have a better outcome following radical radiotherapy/chemo-radiotherapy. Intratumoral-activated HIF- and CA9-related pathways characterize immunologically cold tumors and may be used as targets for therapeutic interventions.

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Background/Aim: Hypofractionated accelerated radiotherapy (HypoAR) is widely applied for the treatment of early laryngeal cancer. Its role in locally advanced head-neck cancer (LA-HNC) is unexplored. Patients and Methods: We present results of a prospective trial on 124 patients with LA-HNC, treated with radio-chemotherapy with three different HypoAR fractionations . Results: Protraction of the overall treatment time due to oropharyngeal mucositis was enforced in 18/57 laryngeal, 6/19 nasopharyngeal, and 15/48 cancer patients with other tumors. Regarding late toxicities, laryngeal edema grade 3 was noted in 5/57 patients with laryngeal cancer, while severe dysphagia was noted in 4/124 and tracheoesophageal fistula formation in 1/124 patients. The complete response rates obtained were 73%, 84%, and 67% in patients with laryngeal, nasopharyngeal, and other tumors, respectively. The 3-year locoregional progression-free survival was 58%, 73%, and 55%, respectively. Conclusion: HypoAR chemoradiotherapy is feasible, with acceptable early and late radiotherapy toxicities, response rates and LPFS.The justified, to a certain point, phobia spread over the 1980s and 1990s regarding the severity of late complications from hypofractionation, promoted the switch of clinical trials towards hyperfractionated regimens. Hypofractionation was reduced to a clinical tool for overloaded radiotherapy departments or was used as a research tool by few heretics. In his 'lessons from complications' paper, G.H. Fletcher appeared convinced that hypofractionation produces unacceptable late toxicities in breast cancer (1). However, the whole breast's dose in the image case presented in the article was equal to a normalized biological total dose of 60Gy (5 fractions of 670 cGy). This dose would have produced similarly poor cosmetic results even if given with conventional fractionation. Today, hypofractionated and accelerated radiotherapy (HypoAR) is the standard of care for breast cancer patients (2, 3).The reconsideration of hypofractionation became feasible due to the technological advances in radiotherapy and, most importantly, the optimized calculation of the biological radiation dose (according to the linear-quadratic model formulas). Moreover, radiobiological analysis of large clinical data dissolved the long-lasting misconception that all tumors have a high α/β-value, challenging the supremacy of small doses per fraction. Today, HypoAR has gained the trust of Radiation Oncologists worldwide for the treatment of breast, prostate, and rectal cancer (2-6). The use of Stereotactic Body Radiotherapy SBRT, applying super-hypofractionated regimens, is gradually increasing, as the publications of favorable experiences are rapidly increasing (7).Regarding head-neck cancer, HypoAR is considered the standard of care for early laryngeal cancer (8). HypoAR is more effective than conventional radiotherapy (ConvRT) or even surgery for early laryngeal carcinomas (9). However, the overall world experience on HypoAR in locally advanced head-neck cancer (L...