Background/Objectives: Lung cancer is the leading cause of cancer-related mortality worldwide. Accurate radiotherapy (RT) planning alongside chemotherapy and immunotherapy is critical for improving treatment outcomes for inoperable non-metastatic cases. Conventional computed tomography (CT)-based planning may be inadequate for accurately identifying tumor margins and the location of nodal disease. We investigated whether ¹⁸F-labeled fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET-CT) imaging can assist in target volume delineation for primary, nodal, and metastatic disease in the RT planning and overall therapeutic planning of patients. Methods: In this single-center, prospective study, we recruited 34 patients with histologically confirmed locally advanced non-small-cell lung carcinoma (NSCLC). All patients underwent ¹⁸F-FDG PET-CT-based RT simulation. Two sequential RT plans were created by the same radiation oncologist: one based on CT alone and the other PET-CT. Planning target volumes (PTVs) and PET-CT-guided adjustments were analyzed to assess their impact. Standardized protocols for immobilization, imaging, target delineation, and dose prescription were applied. Results: A total of 34 patients (31 males and 3 females) were recruited in the study. ¹⁸F-FDG PET-CT detected distant metastases in 7/34 (20.6%) patients, altering the overall therapeutic plan in 4/34 (11.8%) and allowing radical RT in 3 of them who had oligometastatic disease (8.8%). It modified RT planning in 26/34 (76.5%) patients and clarified malignancy in atelectatic areas. Nodal involvement was identified in 3/34 patients (8.8%) and excluded in 3/34 cases, avoiding unnecessary nodal irradiation. Additional involved nodes were revealed in 12/34 (35.3%) patients, requiring dose escalation. Overall, changes to the tumor PTV were made in 23/30 (76.6%) and to the nodal PTV in 19/30 (63.3%) cases (p < 0.0001). Primary tumor and nodal PTVs increased in 20/34 (66.7%) and 13/34 (43.3%), respectively. Conclusions: ¹⁸F-FDG PET-CT significantly improves RT planning by more precisely defining tumor and nodal volumes, identifying undetected lesions, and guiding dose adaptation. Larger long-term studies are required to confirm potential locoregional control and survival improvements.

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.

Radiotherapy (RT)-induced lymphopenia may hinder the anti-tumor immune response. Preoperative RT or chemo-RT (CRT) for locally advanced rectal cancer is a standard therapeutic approach, while immunotherapy has been approved for mismatch repair-deficient rectal tumors. We retrospectively analyzed 98 rectal adenocarcinoma patients undergoing neoadjuvant CRT with VMAT (groups A, B, C) or IMRT (group D) techniques, with four different RT schemes: group A (n = 24): 25 Gy/5 Gy/fraction plus a 0.2 Gy/fraction rectal tumor boost; group B (n = 22): 34 Gy/3.4 Gy/fraction, with a 1-week treatment break after the first five RT fractions; group C (n = 20): 46 Gy/2 Gy/fraction plus a 0.2 Gy/fraction rectal tumor boost; group D (n = 32): 45 Gy/1.8 Gy/fraction followed by 5.4 Gy/1.8 Gy/fraction to the rectal tumor. We examined the effect of the time-corrected normalized total dose (NTD-T) to the BM on lymphopenia. Groups A and B (hypofractionated RT) had significantly higher lymphocyte counts (LCs) after RT than groups C and D (p < 0.03). An inverse association between the LCs after RT and NTD-T was demonstrated (p = 0.01). An NTD-T threshold of 30 Gy delivered to 30% of the BM volume emerged as a potential constraint for RT planning, which could be successfully integrated in the RT plan. Hypofractionated and accelerated RT schemes, and BM-sparing techniques may reduce lymphocytic damage and prove critical for immuno-RT clinical trials.

We report long-term results (median follow-up 12 years) of hypofractionated accelerated radiotherapy (HypoAR) in patients treated with breast-conserving surgery. In total, 367 women were treated with HypoAR. Axillary and supraclavicular area (ASA) were treated in patients with involved nodes. In total, 290 patients (scheme A) received 3.5 Gy/day ×10 fractions (breast/ASA) followed by two 4 Gy fractions with electrons to the affected breast quadrant within 16 days. In total, 77 patients (Scheme B) received 2.7 Gy/day for 16 consecutive fractions (breast/ASA) within 22 days, while concurrently, the affected breast quadrant received an electron booster dose of 0.8 Gy for the first 13 fractions. Amifostine was offered to 252/367 patients. Early radiation toxicity was minimal. Regarding late toxicities, symptomatic breast edema was noted in 2.2%, asymptomatic breast fibrosis in 1.9%, and arm lymphedema in 3.7% of patients. Amifostine reduced early radiation dermatitis (p = 0.001). In total, 2.2% of patients developed contralateral breast and 1.6% other carcinomas. Locoregional recurrence (LR) occurred in 3.1% of patients (0% for in situ carcinomas). Positive margins after surgery, extracapsular node invasion, and HER2-enriched/triple-negative tumors were linked with significantly worse LR-free survival. The involvement of more than three nodes and luminal type other than A were independent prognostic variables of metastasis and death events. HypoAR delivering a biological dose of 50–52 Gy to the breast/ASA is a safe and effective therapy for patients treated with conservative surgery. The risk of carcinogenesis is low. Positive surgical margins, extracapsular node invasion, and HER2-enriched/triple-negative phenotypes appear as a cluster of features linked with a higher risk for locoregional relapse.

Introduction: Adult medulloblastoma is a rare disease. Due to the length of the body areas demanding irradiation, medulloblastoma is a challenging malignancy for the development of advanced radiotherapy techniques. Case Report: We describe a volumetric modulated arc therapy (VMAT) technique applied under image-guided radiation therapy (IGRT) for craniospinal irradiation, offered to a patient with high risk medulloblastoma, together with cisplatin/temozolomide chemotherapy. Three areas of irradiation (cranial, thoracic, and lumbar) were defined, with shifting the gaps between them at a weekly basis (two shifts within the three weeks of therapy). The biological equivalent “normalized total dose” (NTD) to the craniospinal axis and the gaps between the three VMAT-treated areas were calculated for α/β-ratio of 2 Gy, and all the data from dose volume histograms (DVHs) are shown. Conclusion: The technique is reliable delivering with safety and accuracy the desirable radiation dose, with biologically and oncologically acceptable dose-deviations within the field-gaps. The tolerance of the radiochemotherapy regimen was excellent.