In Response to "Acute Oral Mucositis During Hypo-Fractionated Radiation in Squamous Cell Carcinoma of Oral Cavity".

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[Spatially fractionated radiotherapy : introduction into clinical practice]. / Radiothérapie fractionnée dans l'espace : introduction en pratique clinique.

Spatially fractionated radiotherapy is a new concept involving partial irradiation of tumor volumes. Different techniques are described: mini-beam and micro-beam radiotherapy (pre-clinical) and LATTICE radiotherapy (L-RT) (clinical). Although L-RT is emergent in clinical practice and its evidence is still limited, it has still revealed excellent outcomes. At least three clinical situations can be discussed: definitive palliative radiotherapy, dose escalation (boost) or salvage radiotherapy. The interaction between L-RT and the immune system is still under investigation. Preclinical observations have already demonstrated a strong interaction, with tumor response dependent on immune system stimulation and the generation of an abscopal effect.

La radiothérapie fractionnée dans l'espace est un nouveau concept consistant en une irradiation partielle des volumes tumoraux. Plusieurs techniques sont ainsi décrites : les radiothérapies mini-beam et micro-beam (pré-clinique) et la radiothérapie LATTICE (L-RT) (clinique). Bien que la L-RT soit relativement nouvelle dans la pratique clinique et que les preuves quant à son utilisation soient encore limitées, elle montre des résultats prometteurs. Au moins trois situations cliniques peuvent être examinées en détail : la radiothérapie palliative définitive, l'escalade de dose (boost) ou encore la radiothérapie de sauvetage. L'interaction entre la L-RT et le système immunitaire est encore en cours d'investigation, mais des observations précliniques ont déjà démontré une interaction forte, avec notamment la dépendance de la réponse tumorale à la stimulation du système immunitaire et la génération d'un effet abscopal.

Tuning spatially fractionated radiotherapy dose profiles using the moiré effect.

Spatially Fractionated Radiotherapy (SFRT) has demonstrated promising potential in cancer treatment, combining the advantages of reduced post-radiation effects and enhanced local control rates. Within this paradigm, proton minibeam radiotherapy (pMBRT) was suggested as a new treatment modality, possibly producing superior normal tissue sparing to conventional proton therapy, leading to improvements in patient outcomes. However, an effective and convenient beam generation method for pMBRT, capable of implementing various optimum dose profiles, is essential for its real-world application. Our study investigates the potential of utilizing the moiré effect in a dual collimator system (DCS) to generate pMBRT dose profiles with the flexibility to modify the center-to-center distance (CTC) of the dose distribution in a technically simple way.We employ the Geant4 Monte Carlo simulations tool to demonstrate that the angle between the two collimators of a DCS can significantly impact the dose profile. Varying the DCS angle from 10 ∘ to 50 ∘ we could cover CTC ranging from 11.8 mm to 2.4 mm, respectively. Further investigations reveal the substantial influence of the multi-slit collimator's (MSC) physical parameters on the spatially fractionated dose profile, such as period (CTC), throughput, and spacing between MSCs. These findings highlight opportunities for precision dose profile adjustments tailored to specific clinical scenarios.The DCS capacity for rapid angle adjustments during the energy transition stages of a spot scanning system can facilitate dynamic alterations in the irradiation profile, enhancing dose contrast in normal tissues. Furthermore, its unique attribute of spatially fractionated doses in both lateral directions could potentially improve normal tissue sparing by minimizing irradiated volume. Beyond the realm of pMBRT, the dual MSC system exhibits remarkable versatility, showing compatibility with different types of beams (X-rays and electrons) and applicability across various SFRT modalities.Our study illuminates the dual MSC system's potential as an efficient and adaptable tool in the refinement of pMBRT techniques. By enabling meticulous control over irradiation profiles, this system may expedite advancements in clinical and experimental applications, thereby contributing to the evolution of SFRT strategies.

Spatially fractionated radiation therapy: a critical review on current status of clinical and preclinical studies and knowledge gaps.

Spatially fractionated radiation therapy (SFRT) is a therapeutic approach with the potential to disrupt the classical paradigms of conventional radiation therapy. The high spatial dose modulation in SFRT activates distinct radiobiological mechanisms which lead to a remarkable increase in normal tissue tolerances. Several decades of clinical use and numerous preclinical experiments suggest that SFRT has the potential to increase the therapeutic index, especially in bulky and radioresistant tumors. To unleash the full potential of SFRT a deeper understanding of the underlying biology and its relationship with the complex dosimetry of SFRT is needed. This review provides a critical analysis of the field, discussing not only the main clinical and preclinical findings but also analyzing the main knowledge gaps in a holistic way.

Stereotactic body radiotherapy in lung cancer: a contemporary review.

The treatment of early stage non-small cell lung cancer (NSCLC) has improved enormously in the last two decades. Although surgery is not the only choice, lobectomy is still the gold standard treatment type for operable patients. For inoperable patients stereotactic body radiotherapy (SBRT) should be offered, reaching very high local control and overall survival rates. With SBRT we can precisely irradiate small, well-defined lesions with high doses. To select the appropriate fractionation schedule it is important to determine the size, localization and extent of the lung tumor. The introduction of novel and further developed planning (contouring guidelines, diagnostic image application, planning systems) and delivery techniques (motion management, image guided radiotherapy) led to lower rates of side effects and more conformal target volume coverage. The purpose of this study is to summarize the current developments, randomised studies, guidelines about lung SBRT, with emphasis on the possibility of increasing local control and overall rates in "fit," operable patients as well, so SBRT would be eligible in place of surgery.

Radiation Therapy Oncology Group 8502 "QUAD shot" regimen using volumetric modulated arc therapy for incurable head and neck cancer.

OBJECTIVES: We aimed to evaluate the outcomes of the Radiation Therapy Oncology Group 8502 "QUAD shot" regimen using volumetric modulated arc therapy (VMAT) for incurable head and neck cancer (HNC). MATERIALS AND METHODS: We included 105 patients with HNC in the study, undergoing at least one QUAD shot regimen cycle. We planned the radiotherapy using VMAT with 6 MV photons. One QUAD shot cycle included 14.8 Gy in 4 fractions with at least 6-hour intervals over 2 consecutive days, repeated every 3-6 weeks up to 3 cycles. RESULTS: We completed 1, 2, and 3 cycles in 11 (10 %), 17 (16 %), and 77 (73 %) patients, respectively. We concurrently performed systemic therapy in 13 (12 %) patients. Tumor response was observed in 92 (88 %) patients and at least one symptom relief in 51 (71 %) of 72 patients. We observed an overall response (tumor response or symptom relief) in 98 (93 %) patients with all patients who completed 3 cycles achieving it. The median overall survival (OS) was 6.8 months. Our multivariate analysis revealed that non-squamous cell carcinoma (p < 0.001), T category of 0-2 (p = 0.021), and 3 QUAD shot cycles (p < 0.001) were independent prognostic factors of better OS. We observed Grade 3 toxicity in 2 (2 %) patients while no ≥ Grade 4 acute or ≥ Grade 3 late toxicity. CONCLUSIONS: The QUAD shot regimen using VMAT exerts appropriate palliative effect in patients with incurable HNC. Treatment with higher QUAD shot cycle number would be recommended for better treatment outcomes.

Optimal hypofractionated radiation therapy schemes for early-stage hepatocellular carcinoma.

PURPOSE: Stereotactic body radiation therapy (SBRT) has been emerging as an efficacious and safe treatment modality for early-stage hepatocellular carcinoma (HCC), but optimal fractionation regimens are unknown. This study aims to analyze published clinical tumor control probability (TCP) data as a function of biologically effective dose (BED) and to determine radiobiological parameters and optimal fractionation schemes for SBRT and hypofractionated radiation therapy of early-stage HCC. MATERIAL AND METHODS: Clinical 1- to 5-year TCP data of 4313 patients from 41 published papers were collected for hypofractionated radiation therapy at 2.5-4.5 Gy/fraction and SBRT of early-stage HCC. BED was calculated at isocenter using three representative radiobiological models developed per the Hypofractionated Treatment Effects in the Clinic (HyTEC) initiative. Radiobiological parameters were determined from a fit to the TCP data using the least χ2 method with one set of model parameters regardless of tumor stages or Child-Pugh scores A and B. RESULTS: The fits to the clinical TCP data for SBRT of early-stage HCC found consistent α/ß ratios of about 14 Gy for all three radiobiological models. TCP increases sharply with BED and reaches an asymptotic maximal plateau, which results in optimal fractionation schemes of least doses to achieve asymptotic maximal tumor control for SBRT and hypofractionated radiation therapy of early-stage HCC that are found to be model-independent. CONCLUSION: From the fits to the clinical TCP data, we presented the first determination of radiobiological parameters and model-independent optimal fractionation regimens in 1-20 fractions to achieve maximal tumor control whenever safe for SBRT and hypofractionated radiation therapy of early-stage HCC. The determined optimal fractionation schemes agree well with clinical practice for SBRT of early-stage HCC. However, most existing hypofractionated radiation therapy schemes of 3-5 Gy/fraction are not optimal, higher doses are required to maximize tumor control, further validation of these findings is essential with clinical TCP data.

Dose-response of localized renal cell carcinoma after stereotactic body radiation therapy: A meta-analysis.

BACKGROUND: Stereotactic ablative radiation therapy (SBRT) is an emerging treatment option for primary renal cell carcinoma (RCC), particularly in patients who are unsuitable for surgery. The aim of this review is to assess the effect of increasing the biologically equivalent dose (BED) via various radiation fractionation regimens on clinical outcomes. METHODS: A literature search was conducted in PubMed (Medline), EMBASE, and the Cochrane Library for studies published up to October 2023. Studies reporting on patients with localized RCC receiving SBRT were included to determine its effectiveness on local control, progression-free survival, and overall survival. A random effects model was used to meta-regress clinical outcomes relative to the BED for each study and heterogeneity was assessed by I2. RESULTS: A total of 724 patients with RCC from 22 studies were included, with a mean age of 72.7 years (range: 44.0-81.0). Local control was excellent with an estimate of 99 % (95 %CI: 97-100 %, I2 = 19 %), 98 % (95 %CI: 96-99 %, I2 = 8 %), and 94 % (95 %CI: 90-97 %, I2 = 11 %) at one year, two years, and five years respectively. No definitive association between increasing BED and local control, progression-free survival and overall survival was observed. No publication bias was observed. CONCLUSIONS: A significant dose response relationship between oncological outcomes and was not identified, and excellent local control outcomes were observed at the full range of doses. Until new evidence points otherwise, we support current recommendations against routine dose escalation beyond 25-26 Gy in one fraction or 42-48 Gy in three fractions, and to consider de-escalation or compromising target coverage if required to achieve safe organ at risk doses.

Fractionated stereotactic radiotherapy in craniopharyngiomas: A systematic review and single arm meta-analysis.

INTRODUCTION: Numerous studies have demonstrated Fractionated Stereotactic Radiotherapy's (FSRT) effectiveness in tumor control post-resection for craniopharyngiomas. Nevertheless, past literature has presented conflicting findings particularly regarding endocrine and visual function outcomes. This study aims to elucidate FSRT's efficacy and safety for this population. METHODS: Adhering to PRISMA, a systematic review and meta-analyses was conducted. Included studies had to report the effects of FSRT for treating craniopharyngiomas in a sample greater than four patients, addressing at least one of the outcomes of interest: improvement in visual acuity or field, new-onset hypopituitarism, effectiveness, and tumor progression. Relative risk with 95% confidence intervals were used to assess the outcomes. RESULTS: After retrieving a total of 1292 studies, 10 articles met the predefined criteria and thus were finally selected, amounting to a total of 256 patients. The improvement in visual acuity was estimated at 45% (95% CI: 6-83%), while the improvement in the visual field was 22% (95% CI: 0-51%). Regarding endocrine function, the new-onset hypopituitarism rate was found to be 5% (95% CI: 0-11%). Relative to FSRT effectiveness, the pooled estimate of the complete tumor response rate was 17% (95% CI: 4-30%), and the tumor progression rate was 7% (95% CI: 1-13%). Also, a 3-year progression-free survival rate of 98% (95% CI: 95-100%) was obtained. CONCLUSION: Despite limitations and risks, FSRT shows promise as a viable therapeutic option for craniopharyngiomas, offering notable benefits for visual functions and tumor control. Further research is required to better understand the associated risks, benefits, and clinical utility.

Cancer-specific dose and fractionation schedules in stereotactic body radiotherapy for oligometastatic disease: An interim analysis of the EORTC-ESTRO E2-RADIatE OligoCare study.

BACKGROUND AND INTRODUCTION: Optimal dose and fractionation in stereotactic body radiotherapy (SBRT) for oligometastatic cancer patients remain unknown. In this interim analysis of OligoCare, we analyzed factors associated with SBRT dose and fractionation. MATERIALS AND METHODS: Analysis was based on the first 1,099 registered patients. SBRT doses were converted to biological effective doses (BED) using α/ß of 10 Gy for all primaries, and cancer-specific α/ß of 10 Gy for non-small cell lung and colorectal cancer (NSCLC, CRC), 2.5 Gy for breast cancer (BC), or 1.5 Gy for prostate cancer (PC). RESULTS: Of the interim analysis population of 1,099 patients, 999 (99.5 %) fulfilled inclusion criteria and received metastasis-directed SBRT for NSCLC (n = 195; 19.5 %), BC (n = 163; 16.3 %), CRC (n = 184; 18.4 %), or PC (n = 457; 47.5 %). Two thirds of patients were treated for single metastasis. Median number of fractions was 5 (IQR, 3-5) and median dose per fraction was 9.7 (IQR, 7.7-12.4) Gy. The most frequently treated sites were non-vertebral bone (22.8 %), lung (21.0 %), and distant lymph node metastases (19.0 %). On multivariate analysis, the dose varied significantly for primary cancer type (BC: 237.3 Gy BED, PC 300.6 Gy BED, and CRC 84.3 Gy BED), and metastatic sites, with higher doses for lung and liver lesions. CONCLUSION: This real-world analysis suggests that SBRT doses are adjusted to the primary cancers and oligometastasis location. Future analysis will address safety and efficacy of this site- and disease-adapted SBRT fractionation approach (NCT03818503).

21 Gy single fraction prostate HDR brachytherapy: 5-year results of a single institution prospective pilot study.

PURPOSE: To present the outcome and toxicity results of a prospective trial of 21 Gy single fraction high-dose-rate (HDR) brachytherapy for men with low- or intermediate-risk prostate cancer. METHODS AND MATERIALS: Patients were treated according to an IRB-approved prospective study of single fraction HDR brachytherapy. Eligible patients had low- or intermediate-risk prostate cancer with tumor stage ≤ T2b, PSA ≤ 15, and Gleason score ≤ 7. Patients underwent trans-rectal ultrasound-guided trans-perineal implant of the prostate followed by single fraction HDR brachytherapy to a dose of 21 Gy. The primary endpoint was grade ≥ 2 urinary/GI toxicity rates. RESULTS: Twenty-six patients were enrolled with a median follow up of 5.1 years and median age of 64 years. 88.5% of patients had T1 disease, 15.4% had Gleason score 6 (84.6% Gleason 7), and median pre-treatment PSA was 5.0 ng/mL. Acute and chronic grade ≥ 2 urinary toxicity rates were 38.5% and 38.5%, respectively. There were no grade ≥ 2 acute or chronic GI toxicities. Six (23.1%) patients experienced biochemical failure, six (23.1%) patients experienced radiographic local failure, and five (19.2%) patients had biopsy-proven local failure. No patients developed regional lymph node recurrence or distant metastasis. 5-year overall survival and cause-specific survival were 96.2% and 100%, respectively. CONCLUSIONS: 21 Gy single fraction HDR brachytherapy was associated with modestly higher-than-anticipated chronic urinary toxicity, as well as high biochemical and local failure rates. The results from this prospective pilot study do not support the use of this regimen in standard clinical practice.

Are oral cancers effectively palliated with radiotherapy? Outcomes of treatment with a modified QUAD SHOT regimen.

BACKGROUND: This study assessed a palliative radiotherapy regimen using daily radiation over 4 days for three courses in inoperable head and neck cancers, emphasizing oral primary cancers. METHODS: Retrospective data of 116 patients treated with a daily dose of 3.6-3.7 Gy in four fractions over 4 days to a total of three courses, with a 2-week gap after every course, were analyzed for survival outcomes. A subgroup analysis was done for oral cancer. RESULTS: Ninety-nine (85%) completed three courses. Overall subjective response rate was 77%. Median overall survival and progression-free survival were 12 months (95% confidence interval [CI]: 8-20) and 8 months (95% CI: 6-10), with numerically higher overall survival in oral cancer. The treatment was well tolerated, with no on-treatment hospitalization or grade 3-4 toxicities. CONCLUSION: The modified QUAD SHOT regimen is practical for palliation in head and neck cancers.

Late genitourinary toxicity in salvage radiotherapy for prostate cancer after radical prostatectomy: impact of daily fraction doses.

OBJECTIVE: To evaluate the impact of daily fraction doses on late genitourinary (GU) toxicity after salvage radiotherapy (SRT) for prostate cancer. METHODS: This multi-institutional retrospective study included 212 patients who underwent SRT between 2008 and 2018. All patients received image-guided intensity-modulated SRT at a median dose of 67.2 Gy in 1.8-2.3 Gy/fraction. The cumulative rates of late grade ≥2 GU and gastrointestinal (GI) toxicities were compared using Gray test, stratified by the ≤2.0 Gy/fraction (n = 137) and ≥2.1 Gy/fraction groups (n = 75), followed by multivariate analyses. The total dose was represented as an equivalent dose in 2-Gy fractions (EQD2) with α/ß = 3 Gy. RESULTS: After a median follow-up of 63 months, the cumulative rates of 5-year late grade ≥2 GU and GI toxicities were 14% and 2.5%, respectively. The cumulative rates of 5-year late grade ≥2 GU toxicity in the ≥2.1 Gy/fraction and ≤2.0 Gy/fraction groups were 22% and 10%, respectively (P = .020). In the multivariate analysis, ≥2.1 Gy/fraction was still associated with an increased risk of late grade ≥2 GU toxicity (hazard ratio, 2.37; 95% confidence interval, 1.12-4.99; P = .023), while the total dose was not significant. CONCLUSION: The present results showed that ≥2.1 Gy/fraction resulted in a higher incidence of late grade ≥2 GU toxicity in SRT. ADVANCES IN KNOWLEDGE: The impact of fraction doses on late GU toxicity after SRT remains unknown. The results suggest that higher fraction doses may increase the risk of late GU toxicity in SRT.

Radiation-induced bystander effect on the brain after fractionated spinal cord irradiation of aging rats.

We investigated the influence of the so-called bystander effect on metabolic and histopathological changes in the rat brain after fractionated spinal cord irradiation. The study was initiated with adult Wistar male rats (n = 20) at the age of 9 months. The group designated to irradiation (n = 10) and the age-matched control animals (n = 10) were subjected to an initial measurement using in vivo proton magnetic resonance spectroscopy (1H MRS) and magnetic resonance imaging (MRI). After allowing the animals to survive until 12 months, they received fractionated spinal cord irradiation with a total dose of 24 Gy administered in 3 fractions (8 Gy per fraction) once a week on the same day for 3 consecutive weeks. 1H MRS and MRI of brain metabolites were performed in the hippocampus, corpus striatum, and olfactory bulb (OB) before irradiation (9-month-old rats) and subsequently 48 h (12-month-old) and 2 months (14-month-old) after the completion of irradiation. After the animals were sacrificed at the age of 14 months, brain tissue changes were investigated in two neurogenic regions: the hippocampal dentate gyrus (DG) and the rostral migratory stream (RMS). By comparing the group of 9-month-old rats and individuals measured 48 h (at the age of 12 months) after irradiation, we found a significant decrease in the ratio of total N-acetyl aspartate to total creatine (tNAA/tCr) and gamma-aminobutyric acid to tCr (GABA/tCr) in OB and hippocampus. A significant increase in myoinositol to tCr (mIns/tCr) in the OB persisted up to 14 months of age. Proton nuclear magnetic resonance (1H NMR)-based plasma metabolomics showed a significant increase in keto acids and decreased tyrosine and tricarboxylic cycle enzymes. Morphometric analysis of neurogenic regions of 14-month-old rats showed well-preserved stem cells, neuroblasts, and increased neurodegeneration. The radiation-induced bystander effect more significantly affected metabolite concentration than the distribution of selected cell types.

Histology-driven hypofractionated radiation therapy schemes for early-stage lung adenocarcinoma and squamous cell carcinoma.

BACKGROUND AND PURPOSE: Histology was found to be an important prognostic factor for local tumor control probability (TCP) after stereotactic body radiotherapy (SBRT) of early-stage non-small-cell lung cancer (NSCLC). A histology-driven SBRT approach has not been explored in routine clinical practice and histology-dependent fractionation schemes remain unknown. Here, we analyzed pooled histologic TCP data as a function of biologically effective dose (BED) to determine histology-driven fractionation schemes for SBRT and hypofractionated radiotherapy of two predominant early-stage NSCLC histologic subtypes adenocarcinoma (ADC) and squamous cell carcinoma (SCC). MATERIAL AND METHODS: The least-χ2 method was used to fit the collected histologic TCP data of 8510 early-stage NSCLC patients to determine parameters for a well-developed radiobiological model per the Hypofractionated Treatment Effects in the Clinic (HyTEC) initiative. RESULTS: A fit to the histologic TCP data yielded independent radiobiological parameter sets for radiotherapy of early-stage lung ADC and SCC. TCP increases steeply with BED and reaches an asymptotic maximal plateau, allowing us to determine model-independent optimal fractionation schemes of least doses in 1-30 fractions to achieve maximal tumor control for early-stage lung ADC and SCC, e.g., 30, 44, 48, and 51 Gy for ADC, and 32, 48, 54, and 58 Gy for SCC in 1, 3, 4, and 5 fractions, respectively. CONCLUSION: We presented the first determination of histology-dependent radiobiological parameters and model-independent histology-driven optimal SBRT and hypofractionated radiation therapy schemes for early-stage lung ADC and SCC. SCC requires substantially higher radiation doses to maximize tumor control than ADC, plausibly attributed to tumor genetic diversity and microenvironment. The determined optimal SBRT schemes agree well with clinical practice for early-stage lung ADC. These proposed optimal fractionation schemes provide first insights for histology-based personalized radiotherapy of two predominant early-stage NSCLC subtypes ADC and SCC, which require further validation with large-scale histologic TCP data.

Radiation Therapy Technology Advances and Mitigation of Subsequent Neoplasms in Childhood Cancer Survivors.

PURPOSE: In this Pediatric Normal Tissue Effects in the Clinic (PENTEC) vision paper, challenges and opportunities in the assessment of subsequent neoplasms (SNs) from radiation therapy (RT) are presented and discussed in the context of technology advancement. METHODS AND MATERIALS: The paper discusses the current knowledge of SN risks associated with historic, contemporary, and future RT technologies. Opportunities for research and SN mitigation strategies in pediatric patients with cancer are reviewed. RESULTS: Present experience with radiation carcinogenesis is from populations exposed during widely different scenarios. Knowledge gaps exist within clinical cohorts and follow-up; dose-response and volume effects; dose-rate and fractionation effects; radiation quality and proton/particle therapy; age considerations; susceptibility of specific tissues; and risks related to genetic predisposition. The biological mechanisms associated with local and patient-level risks are largely unknown. CONCLUSIONS: Future cancer care is expected to involve several available RT technologies, necessitating evidence and strategies to assess the performance of competing treatments. It is essential to maximize the utilization of existing follow-up while planning for prospective data collection, including standardized registration of individual treatment information with linkage across patient databases.

A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

BACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. FUNDING: Cancer Research UK, NIHR, MRC.

Hypofractionated stereotactic re-irradiation for progressive glioblastoma: twelve years' experience of a single center.

PURPOSE: We aimed to evaluate the prognostic factors and the role of stereotactic radiotherapy (SRT) as a re-irradiation technique in the management of progressive glioblastoma. METHODS: The records of 77 previously irradiated glioblastoma patients who progressed and received second course hypofractionated SRT (1-5 fractions) between 2009 and 2022 in our department were evaluated retrospectively. Statistical Package for the Social Sciences (SPSS) version 23.0 (IBM, Armonk, NY, USA) was utilized for all statistical analyses. RESULTS: The median time to progression from the end of initial radiotherapy was 14 months (range, 6-68 months). The most common SRT schedule was 30 Gy (range, 18-50 Gy) in 5 fractions (range, 1-5 fractions). The median follow-up after SRT was 9 months (range, 3-80 months). One-year overall (OS) and progression-free survival (PFS) rates after SRT were 46% and 35%, respectively. Re-irradiation dose and the presence of pseudoprogression were both significant independent positive prognostic factors for both OS (p = 0.009 and p = 0.04, respectively) and PFS (p = 0.008 and p = 0.04, respectively). For PFS, progression-free interval > 14 months was also a prognostic factor (p = 0.04). The treatment was well tolerated without significant acute toxicity. During follow-up, radiation necrosis was observed in 17 patients (22%), and 14 (82%) of them were asymptomatic. CONCLUSION: Hypofractionated SRT is an effective treatment approach for patients with progressive glioblastoma. Younger patients who progressed later than 14 months, received higher SRT doses, and experienced pseudoprogression following SRT had improved survival rates.