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Background/Aim: Radiotherapy is widely accepted as the treatment of choice for early glottic squamous cell carcinoma (EGSCC), although it varies greatly with respect to dose, dose per fraction, and treatment techniques. The study aim was to evaluate the use of accelerated fractionation strategy (AFS) for EGSCC in standard clinical practice. Patients and Methods: Patients treated with definitive radiotherapy for EGSCC between 2008 and 2019 were retrospectively identified and received either conventional fractionation, hypofractionation, or hyperfractionation. Results: One hundred six patients were analyzed, and 19, 71, and 16 patients underwent conventional fractionation, hypofractionation, and hyperfractionation, respectively. The median follow-up was 56 months. The 5-year local control and overall survival rates were 79% and 83%; 78% and 79%; and 87% and 77%, respectively, and no significant difference was observed between the fractionation schedules. Conclusion: Our findings confirmed the utility of AFS in standard clinical practice and support its use for patients with EGSCC.

Background and purpose The standard treatment of glioblastoma patients consists of surgery followed by normofractionated radiotherapy (NFRT) with concomitant and adjuvant temozolomide chemotherapy. Whether accelerated hyperfractionated radiotherapy (HFRT) yields comparable results to NFRT in combination with temozolomide has only sparsely been investigated. The objective of this study was to compare NFRT with HFRT in a multicenter analysis. Materials and methods A total of 484 glioblastoma patients from four centers were retrospectively pooled and analyzed. Three-hundred-ten and 174 patients had been treated with NFRT (30 × 1.8 Gy or 30 × 2 Gy) and HFRT (37 × 1.6 Gy or 30 × 1.8 Gy twice/day), respectively. The primary outcome of interest was overall survival (OS) which was correlated with patient-, tumor- and treatment-related variables via univariable and multivariable Cox frailty models. For multivariable modeling, missing covariates were imputed using multiple imputation by chained equations, and a sensitivity analysis was performed on the complete-cases-only dataset. Results After a median follow-up of 15.7 months (range 0.8–88.6 months), median OS was 16.9 months (15.0–18.7 months) in the NFRT group and 14.9 months (13.2–17.3 months) in the HFRT group (p = 0.26). In multivariable frailty regression, better performance status, gross-total versus not gross-total resection, MGMT hypermethylation, IDH mutation, smaller planning target volume and salvage therapy were significantly associated with longer OS (all p < 0.01). Treatment differences (HFRT versus NFRT) had no significant effect on OS in either univariable or multivariable analysis. Conclusions Since HFRT with temozolomide was not associated with worse OS, we assume HFRT to be a potential option for patients wishing to shorten their treatment time.

Background Although altered protocols that challenge conventional radiation fractionation have been tested in prospective clinical trials, we still have limited understanding of how to select the most appropriate fractionation schedule for individual patients. Currently, the prescription of definitive radiotherapy is based on the primary site and stage, without regard to patient-specific tumor or host factors that may influence outcome. We hypothesize that the proportion of radiosensitive proliferating cells is dependent on the saturation of the tumor carrying capacity. This may serve as a prognostic factor for personalized radiotherapy (RT) fractionation. Methods We introduce a proliferation saturation index (PSI), which is defined as the ratio of tumor volume to the host-influenced tumor carrying capacity. Carrying capacity is as a conceptual measure of the maximum volume that can be supported by the current tumor environment including oxygen and nutrient availability, immune surveillance and acidity. PSI is estimated from two temporally separated routine pre-radiotherapy computed tomography scans and a deterministic logistic tumor growth model. We introduce the patient-specific pre-treatment PSI into a model of tumor growth and radiotherapy response, and fit the model to retrospective data of four non-small cell lung cancer patients treated exclusively with standard fractionation. We then simulate both a clinical trial hyperfractionation protocol and daily fractionations, with equal biologically effective dose, to compare tumor volume reduction as a function of pretreatment PSI. Results With tumor doubling time and radiosensitivity assumed constant across patients, a patient-specific pretreatment PSI is sufficient to fit individual patient response data (R 2  = 0.98). PSI varies greatly between patients (coefficient of variation >128 %) and correlates inversely with radiotherapy response. For this study, our simulations suggest that only patients with intermediate PSI (0.45–0.9) are likely to truly benefit from hyperfractionation. For up to 20 % uncertainties in tumor growth rate, radiosensitivity, and noise in radiological data, the absolute estimation error of pretreatment PSI is <10 % for more than 75 % of patients. Conclusions Routine radiological images can be used to calculate individual PSI, which may serve as a prognostic factor for radiation response. This provides a new paradigm and rationale to select personalized RT dose-fractionation.

Background/Aim: Accelerated hyperfractionation (AHF) is used in head and neck cancer to improve the local control (LC) rate, but reports of outcomes for early-stage GC are limited. The outcomes of radiotherapy (RT) for stage 1 glottic carcinoma (GC) were retrospectively analyzed, comparing AHF and once-daily fractionation (ODF) using 2.0-2.4 Gy. Patients and Methods: A total of 102 patients with stage 1 GC underwent RT alone between 2007 and 2021, with 43 in the AHF group and 59 in the ODF group. A p-value less than 0.05 was considered to indicate a significant difference. Results: The 5-year LC rate was 98% in the AHF group and 91% in the ODF group (p=0.19). During RT, significantly more patients in the AHF group required opioids due to mucositis than in the ODF group (74% vs. 25%, p<0.001), and the rate of aspiration pneumonia tended to be higher in the AHF group than in the ODF group (7% vs. 0%, p=0.072). Conclusion: There was no difference in the LC rate between AHF and ODF for stage 1 GC. Moreover, the AHF group required opioids at a higher rate and tended to have a higher risk of developing aspiration pneumonia.

Anterior commissure is involved in about 20% of early-stage glottic squamous cell carcinomas (EGSCCs). Treatment outcomes and prognostic factors for EGSCC with anterior commissure involvement (ACI) were evaluated by focusing on hyperfractionated radiotherapy (74.4 Gy in 62 fractions). One-hundred and fifty-three patients with T1–T2 EGSCC were included in this study. The median total doses for T1a, T1b, and T2 were 66, 74.4, and 74.4 Gy, respectively. Overall, 49 (32%) patients had T1a, 38 (25%) had T1b, and 66 (43%) had T2 disease. The median treatment duration was 46 days. The median follow-up duration was 5.1 years. The 10-year overall and cause-specific survival rates were 72% and 97%, respectively. The 10-year local control rates were 94% for T1a, 88% for T1b, and 81% for T2 disease. Local control rates in patients with ACI were slightly better than those in patients without ACI with T1a and T1b diseases; however, the difference was not significant. The 10-year laryngeal preservation rate was 96%. Six patients experienced grade 3 mucositis, and four patients had grade 3 dermatitis. Hyperfractionated radiotherapy was effective for T1 disease with ACI, but insufficient for T2 disease with ACI. Our treatment strategy resulted in excellent laryngeal preservation.

To identify the clinical and dosimetric predictors of severe acute radiation esophagitis (RE) in patients with non-small cell lung cancer (NSCLC) treated with accelerated hyperfractionated concurrent chemoradiotherapy (AH-CCRT) with concomitant boost technique. A total of 159 patients who underwent AH-CCRT (64 Gy in 40 fractions twice daily) were retrospectively identified. Severe RE was designated as grade 3 or higher according to the Common Terminology Criteria for Adverse Events, version 4.0. The incidence rate of grade 3 RE was 15.1% (24/159). The multivariate analysis that incorporated the Eastern Cooperative Oncology Group performance status (ECOG PS, ≥1 vs. 0) and the relative esophagus volume irradiated with at least 60 Gy (V ) was optimal. Patients with a V of ≥15% had a 37.8% risk of grade 3 RE compared to a 6.1% risk among those with a V of <15%. ECOG PS (≥1 vs. 0) and the V were found to be significant risk factors for severe RE in NSCLC patients who underwent AH-CCRT.

Background The clinical standard practice of [ 177 Lu]Lu-PSMA-617 therapy is a single injection per treatment cycle, with 6 weeks between cycles. While clinical schedules currently utilize single-bolus cycles, splitting a treatment cycle into multiple smaller injections has demonstrated benefits in other radionuclide therapies, preclinically and in clinical studies. Potential mechanisms for improved therapeutic efficacy include receptor recycling, receptor upregulation, or targeting new cell growth between fractions. This study aims to investigate the effects on tumor size and animal survival, in a mouse model of prostate cancer, of fractionating [ 177 Lu]Lu-PSMA-617 therapy compared to the same total activity in a single injection. Results BALB/c mice bearing subcutaneous LNCaP prostate cancer tumors, below 650 mm 3 in volume, were treated with either 1 × 30 MBq, 2 × 15 MBq (24-hour window), or 2 × 15 MBq (6-day window). SPECT/CT imaging showed a higher, but not significantly so, tumor uptake in the 24-hour window group than in the unfractionated one. Differences in tumor sizes were primarily visible during regrowth after therapy, with significantly smaller relative tumor sizes in the 24-hour window group compared to the unfractionated group day 89–95 post inoculation. The median survival for the 24-hour group (71.5 days) was significantly longer than that of the unfractionated group (46 days; p  = 0.024). The 6-day group tumor sizes and survival came close to the 24-hour one, but was not significantly better than the unfractionated group. Conclusion This study demonstrates that fractionation gives therapeutic benefit in an animal model of [ 177 Lu]Lu-PSMA-617 therapy of prostate cancer for tumors in this size range. A shorter 24-hour window outperformed a longer of 6 d between fractions. The outlook for clinical translation will depend on if the mechanism is relevant at conditions, blood ligand concentration etc., that differs between the animal model and human patients.

Postoperative chemoradiotherapy (POCRT) is the standard treatment for patients with head and neck squamous cell carcinoma (HNSCC) with high-risk features (positive microscopic margins and/or extranodal extensions). We hypothesized that dose escalation using hyperfractionation in intensity-modulated radiotherapy (HF-IMRT) improves POCRT outcomes; however, no prospective trial has assessed the feasibility of POCRT in HF. Therefore, we evaluated the feasibility of POCRT using HF-IMRT. HNSCC patients with positive microscopic margins and/or extranodal extension following surgery were included. HF-IMRT (73.6 Gy in 64 fractions twice daily) was administered along with cisplatin at 40 mg/m2 once a week for seven cycles during radiotherapy. The primary endpoint was the proportion of patients who completed treatment, which included the planned radiotherapy and the administration of ≥200 mg/m2 of cisplatin. Feasibility was defined as the proportion of patients who completed treatment >60% using a one-sided binomial test. Ten patients were registered between October 2021 and April 2023. One patient was excluded because of tumor recurrence before POCRT. The median follow-up time was 18.2 months, and the proportion of patients who completed treatment was 88.9%. The median total dose of cisplatin was 240 mg/m2. The percentage of patients with grade 3 acute non-hematological adverse events was 77.8%. No patient experienced grade 4 or higher acute adverse events or grade 3 or higher late adverse events. POCRT using HF-IMRT is feasible for achieving adequate cisplatin doses and safe radiotherapy in patients with HNSCC.

This review article explores the critical role of time in external radiotherapy, focusing on the concepts of fractionation and spreading. It traces the evolution of radiobiology, highlighting key milestones that have shaped current treatment strategies. The article delves into the four fundamental principles of radiobiology—Repair, Redistribution, Reoxygenation, and Repopulation—and their implications for fractionated radiation therapy. It further discusses the clinical applications of these principles, including hyperfractionated, accelerated, and hypofractionated treatments. This review provides a comprehensive understanding of how the time factor influences the effectiveness of radiotherapy and its impact on healthy and tumor tissues.

Background Limited literature exists on the feasibility and effectiveness of integrating stereotactic ablative radiotherapy (SABR) techniques with hyperfractionated regimens for patients with lung cancer. This study aims to assess whether the SABR technique with hyperfractionation can potentially reduce lung toxicity. Methods We utilized the linear‐quadratic model to find the optimal fraction to maximize the tumor biological equivalent dose (BED) to normal‐tissue BED ratio. Validation was performed by comparing the SABR plans with 50 Gy/5 fractions and hyperfractionationed plans with 88.8 Gy/74 fractions with the same tumor BED and planning criteria for 10 patients with early‐stage lung cancer. Mean lung BED, Lyman–Kutcher–Burman (LKB) normal tissue complication probability (NTCP), critical volume (CV) criteria (volume below BED of 22.92 and 25.65 Gy, and mean BED for lowest 1000 and 1500 cc) and the percentage of the lung receiving 20Gy or more (V20) were compared using the Wilcoxon signed‐rank test. Results The transition point occurs when the tumor‐to‐normal tissue ratio (TNR) of the physical dose equals the TNR of α/β in the BED dose‐volume histogram of the lung. Compared with the hypofractionated regimen, the hyperfractionated regimen is superior in the dose range above but inferior below the transition point. The hyperfractionated regimen showed a lower mean lung BED (6.40 Gy vs. 7.73 Gy) and NTCP (3.50% vs. 4.21%), with inferior results concerning CV criteria and higher V20 (7.37% vs. 7.03%) in comparison with the hypofractionated regimen (p < 0.01 for all). Conclusions The hyperfractionated regimen has an advantage in the high‐dose region of the lung but a disadvantage in the low‐dose region. Further research is needed to determine the superiority between hypo‐ and hyperfractionation. A simple formula to determine the transition point was found. The hypofractionated regimen is superior below this point but inferior above it compared with the hyperfractionated regimen using SABR techniques. In addition, the hyperfractionated regimens appear to be superior to the hypofractionated regimen when comparing LKB model‐estimated NTCP with mean lung BED. Conversely, hypofractionated regimens seem to be better when focusing on critical volume or V20.