Hyperfractionated Radiotherapy Research Articles

Histopathologically confirmed radiation-induced damage of the brain – an in-depth analysis of radiation parameters and spatio-temporal occurrence

BackgroundRadiation-induced damage (RID) after radiotherapy (RT) of primary brain tumors and metastases can be challenging to clinico-radiographically distinguish from tumor progression. RID includes pseudoprogression and radiation necrosis; the latter being irreversible and often associated with severe symptoms. While histopathology constitutes the diagnostic gold standard, biopsy-controlled clinical studies investigating RID remain limited. Whether certain brain areas are potentially more vulnerable to RID remains an area of active investigation. Here, we analyze histopathologically confirmed cases of RID in relation to the temporal and spatial dose distribution.MethodsHistopathologically confirmed cases of RID after photon-based RT for primary or secondary central nervous system malignancies were included. Demographic, clinical, and dosimetric data were collected from patient records and treatment planning systems. We calculated the equivalent dose in 2 Gy fractions (EQD22) and the biologically effective dose (BED2) for normal brain tissue (α/β ratio of 2 Gy) and analyzed the spatial and temporal distribution using frequency maps.ResultsThirty-three patients were identified. High-grade glioma patients (n = 18) mostly received one normofractionated RT series (median cumulative EQD22 60 Gy) to a large planning target volume (PTV) (median 203.9 ccm) before diagnosis of RID. Despite the low EQD22 and BED2, three patients with an accelerated hyperfractionated RT developed RID. In contrast, brain metastases patients (n = 15; 16 RID lesions) were often treated with two or more RT courses and with radiosurgery or fractionated stereotactic RT, resulting in a higher cumulative EQD22 (median 162.4 Gy), to a small PTV (median 6.7 ccm). All (n = 34) RID lesions occurred within the PTV of at least one of the preceding RT courses. RID in the high-grade glioma group showed a frontotemporal distribution pattern, whereas, in metastatic patients, RID was observed throughout the brain with highest density in the parietal lobe. The cumulative EQD22 was significantly lower in RID lesions that involved the subventricular zone (SVZ) than in lesions without SVZ involvement (median 60 Gy vs. 141 Gy, p = 0.01).ConclusionsAccelerated hyperfractionated RT can lead to RID despite computationally low EQD22 and BED2 in high-grade glioma patients. The anatomical location of RID corresponded to the general tumor distribution of gliomas and metastases. The SVZ might be a particularly vulnerable area.

Efficacy and Safety of Radiotherapy Combined with Pyrotinib in the Treatment of HER2-Positive Breast Cancer with Brain Metastases.

To explore the efficacy and safety of pyrotinib combined with different radiotherapy modes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients with brain metastasis (BM). This study is a retrospective analysis of patients diagnosed with BM who underwent treatment with pyrotinib between November 2018 and April 2023. A total of 66 patients were administered radiotherapy in conjunction with pyrotinib (Group A), while 26 patients received pyrotinib as a standalone treatment (Group B). Within Group A, 18 patients underwent conventional fractionated radiotherapy (2Gy/F), while 48 patients received hyperfractionated radiotherapy (HFRT) (≥3Gy/F). The primary endpoints were intracranial progression-free survival (IC-PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR) and clinical benefit rate (CBR). The ORR of Group A was 54.5% (36/66), while the ORR of Group B was 34.6% (9/26) (P= 0.047). The CBR of Group A was 89.4% (59/66) and that of Group B was 69.2% (18/26) (P= 0.041). The IC-PFS between Group A and Group B were 12 months and 8 months, respectively (P< 0.001), and the OS were 20 months and 16 months, respectively (P= 0.065). In Group A, the IC-PFS and OS between the conventional fractionation radiotherapy group and the HFRT group were 10 months and 12 months, respectively (P= 0.001) and 16 months and 24 months, respectively (P< 0.001). No serious adverse reactions were observed in Group A and Group B. For HER2-positive BC patients with BM, it is recommended to adopt the treatment mode of HFRT combined with pyrotinib, which can improve the local control and survival of patients.

EP13.04-04 Preliminary Results of a Prospective Trial of Hypofractionated Radiotherapy Versus Hyperfractionated Radiotherapy for Limited-stage SCLC

EP13.04-04 Preliminary Results of a Prospective Trial of Hypofractionated Radiotherapy Versus Hyperfractionated Radiotherapy for Limited-stage SCLC

Overcoming Radio-Immunotherapy Treatment Resistance through ILT4 Blockade and Reversal of HFRT Induced CXCL1-CXCR2 Axis Activation and Tumor-Associated Macrophage Immunosuppression

Immunotherapy combined with radiotherapy (iRT) has unlimited potential, but up to 60% of cancer patients do not benefit from it. Enhancing the anti-tumor immune stimulatory effect triggered by radiotherapy is the key to overcome iRT resistance. Immunoglobulin-like transcript (ILT) 4 is a potential immune checkpoint molecule, highly expressed in various tumor cells, but its role in radiotherapy is still unknown. This study confirmed the role and molecular mechanism of ILT4 in suppressing radiotherapy immunosuppressive microenvironment formation and promoting tumor radiotherapy resistance. We propose a new therapeutic strategy that block ILT4 to enhance the efficacy of radiotherapy, and cooperate with radiotherapy to reverse immunotherapy resistance. Using multiplex immunohistochemistry, we analyzed ILT4 expression, tumor-associated macrophage (TAM) /T cell phenotype and quantity in tumor patient treated with SBRT. Using mice subcutaneous tumor models, Single-cell RNA sequencing and multiplex flowcytometry, we assessed the role of ILT4 inhibition and hyper-fractionated radiotherapy (HFRT) on preventing tumor growth and immune escape. The molecular signaling and cytokines regulated by ILT4 under HFRT were analyzed by transcriptome sequencing and further verified by molecular experiments. By establishing cancer cell/TAM co-culture system in vitro, using CXCL1 protein or CXCR2 inhibitor and macrophage/CD8+ T cell deletion antibody in vivo, we identified the downstream pathway and cytokine of ILT4 to enhancing HFRT -induced TAM immune response. In the tumor specimens of NSCLC patients treated with SBRT, we found that high ILT4 expression predicted poor progression-free survival and more M2-TAM recruitment. Among the C57BL/6 mice model, ILT4 inhibition in cancer cells reduced HFRT mediated M2-TAMs accumulation, and to sustain activation and proliferation of CD8+ T cells, and eventually suppressed tumor progression. Mechanistically, RT promoted ILT4 expression, which subsequently induced NF-κB pathway activation and CXCL1 secretion to enhance M2-TAMs migration in vitro. Using CXCL1 protein or CXCR2 inhibitor administration, inferring that ILT4 promotes TAMs migration via NF-κB-CXCL1-CXCR2 axis. Consistently, depletion of TAMs blocked the T cell function impairment and radiotherapy resistance induced by ILT4 in vivo. Importantly, targeting ILT4 potentiated the effect of radiotherapy, overcomes radio-immunotherapy treatment resistance. ILT4 mediates HFRT-induced M2-like TAMs recruitment and subsequently T cell response impairment by regulating NF-κB-CXCL1-CXCR2 axis. ILT4 is an attractive drug target for enhancing radiotherapy and overcomes radio-immunotherapy treatment resistance.

HPK1 Inhibition Enhancing HFRT Anti-Tumor Immune Response

Radiation therapy, as one of the canonical treatments for classic tumors, results in impressive clinical responses. Stereotactic body radiotherapy (SBRT) has been increasingly used as one main therapy in early-stage non-small-cell lung cancer (NSCLC). SBRT affords good local tumor control, however, recurrence and metastasis are still the main causes of treatment failure. With the continuous deepening of the relationship between radiotherapy (RT) and immunity, reversing RT induced immunosuppression is considered to be a promising strategy to improve radiotherapy efficacy. Hematopoietic progenitor kinase 1 (HPK1) is mainly expressed in immune cells while rarely expressed in tumor cells. It has been proven to play a negative regulatory role in T cell receptor (TCR) signal. Therefore, we hypothesized that the combination of HPK1 inhibitor with SBRT would boost local and systemic anti-tumor immune responses by potentiating the anti-tumor effects of SBRT. Using Digital Spatial Profiler (DSP), we analyzed HPK1 expression in the tumor specimens of 39 NSCLC patients treated with SBRT. By establishing mice subcutaneous tumor models, we assessed the combination of a HPK1 inhibitor and local hyper-fractionated radiotherapy (HFRT) on local and systemic tumor control and mouse survival. Using Single-cell RNA sequencing, Flow cytometry and pharmacological treatment, we analyzed and verified Tumor-infiltrating lymphocytes (TILs), and excavated the specific mechanism of the HPK1 inhibitor enhancing HFRT -induced anti -tumor immune response. In the tumor specimens of NSCLC patients treated with SBRT, we found that high expression HPK1 in TILs predicted poor progression-free survival (PFS). Among the C57BL/6 mice model, HFRT combined with a HPK1 inhibitor promoted local response, and improved the survival rate of mice, showing better anti-tumor curative effects. We further showed that HFRT promoted CD8+ T cell cytotoxic activity, and also aggravated CD8+ T cell exhaustion. After the intervention of HPK1 small molecular inhibitors, the proportion of exhaustion CD8+T cells was significantly reduced, while CD8+T cell cytotoxic activity was further enhanced in the later period. Single-cell RNA sequencing and pharmacological inhibition of HPK1 revealed that HPK1 mediated the exhaustion of CD8+T cells by regulating RGS16. In abscopal effects preclinical models, BGB-15025 induced obvious abscopal effect. Thus, we demonstrate that HPK1 mediates HFRT-induced CD8+T cell exhaustion by regulating RGS16, and HPK1 is an attractive drug target for enhancing local and systemic radiotherapy.

Conditional Survival Estimates for Malignant Glioma Patients by RPA Class: Secondary Analysis of RTOG 9006

The RTOG recursive partitioning analysis (RPA) for malignant glioma patients is a key prognostic factor correlated with survival for patients with a malignant glioma, which was established using data from RTOG 9006. While such data is useful when counseling patients on survival outcomes at the time of diagnosis, the utility of such data diminishes over time. Conditional survival (CS) is a way to provide 'real-time' estimates of how survival changes over time. The primary objective of this secondary analysis is to report conditional survival estimates for patients with malignant gliomas enrolled on RTOG 9006 stratified by RPA class. RTOG 9006 was a phase III trial of patients diagnosed with malignant gliomas randomized to BCNU and hyper-fractionated radiation therapy (RT) vs. BCNU and conventionally fractionated RT that showed no significant differences in toxicities or oncologic outcomes. We performed a post-hoc analysis of RTOG 9006 using data obtained from the NCI NCTN Data Archive to evaluate conditional survival estimates for different RPA subgroups. Eligible patients included those with a known RPA class who were enrolled on RTOG 9006 (n = 632). Conditional survival estimates from the time of diagnosis and following 1-, 3-, and 5-y of survival were calculated using the Kaplan-Meier method. Cox proportional hazards modeling was performed to evaluate the prognostic significance of treatment arm, histology, extent of surgical resection, and RPA class following 1-, 3-, and 5-y of survival. For RPA Group I (n = 68), OS at 1-y from diagnosis was 95.58%. At 1- (n = 65), 3- (49) and 5-y (42) of survivorship, the chances of surviving an additional 1-y were 84.62, 91.84, 98.62% respectively (See Table 1). RPA class continued to be significantly correlated with survival following 1- and 3-y of survival irrespective of treatment arm. Treatment arm was not significantly correlated with conditional survival at any time point following treatment completion, and there was no interaction between treatment arm and RPA subgroups. Histology was significant at all time points. Conditional risk of death for patients treated for malignant gliomas in RPA Group I remains low at levels similar to those at initial diagnosis. Conditional risk continuously improves for RPA Groups IV-V as patients live longer. In most groups, the lowest survival odds were found in patients who have already survived 1 year.

High Dose Hyperfractionated Thoracic Radiotherapy vs. Standard Dose for Limited Stage Small-Cell Lung Cancer: A Multicenter, Open-Label Randomized, Phase 3 Trial

Limited stage small-cell lung cancer (LS-SCLC) is associated with poor prognosis. We aimed to assess the efficacy and safety of high-dose, hyperfractionated thoracic radiotherapy of 54 Gy in 30 fractions compared with standard dose (45 Gy in 30 fractions) as a first-line treatment for LS-SCLC. The study was an open-label, randomized, phase 3 trial, done at 16 public hospitals in China. Key inclusion criteria were patients aged 18-70 years, with previously histologically or cytologically confirmed LS-SCLC, previously untreated or received 1-2 courses of intravenous cisplatin (75 mg/m²of body-surface area, on day 1 or divided into two days of each cycle) or carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle)and intravenous etoposide (100 mg/m²of body-surface area, on days 1-3 of each cycle), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.Eligible patients were randomly assigned (1:1) to receive volumetric-modulated arc radiotherapy (VMAT) of 45 Gy in 30 fractions or the simultaneous integrated boost VMAT (SIB-VMAT) of 54 Gy in 30 fractions to the primary lung tumor and lymph node metastases starting 0-42 days after the first chemotherapy course. Both groups of patients received thoracic radiotherapy twice per day and 10 fractions per week. Prophylactic cranial radiation (PCI, 25 Gy in 10 fractions) was implemented to patients with responsive disease. The primary endpoint was overall survival. Safety was analyzed in the as-treated population. Between June 30, 2017, and April 6, 2021, 224 eligible patients were enrolled and randomly assigned to 54 Gy (n = 108) or 45 Gy (n = 116). Median follow-up for the primary analysis was 45 months (IQR 41-48). Median overall survival was significantly improved in the 54 Gy group (62.4 months) compared with the 45 Gy group (43.1 months; p = 0.001). Median progression-free survival was significantly improved in the 54 Gy group (30.5 months) compared with the 45 Gy group (16.7 months; p = 0.044). The most common grade 3-4 adverse events were neutropenia (30 [28%] of 108 patients in the 54 Gy group vs 27 [23%] of 116 patients in the 45 Gy group), neutropenic infections (6 [6%] vs 2 [2%]), thrombocytopenia (13 [12%] vs 12 [10%]), anemia (6 [6%] vs 4 [3%]), and esophagitis (1 [1%] vs 3 [3%]). Treatment-related serious adverse events occurred in 9 [8%] patients in the 54 Gy group and 16 [14%] patients in the 45 Gy group. There were one treatment-related deaths in 54 Gy group (myocardial infarction). Compared with standard thoracic radiotherapy dose of 45 Gy, the high dose of 54 Gy improved overall survival and progression-free survival without increasing toxicities in patients with LS-SCLC, supporting twice-daily hyperfractionated thoracic radiotherapy of 54 Gy with concurrent chemotherapy is an alternative treatment option for LS-SCLC. This study is complete and registered with ClinicalTrials.gov, NCT03214003.

Long-Term Results of a Phase II Study of Accelerated Hyperfractionated Thoracic Radiotherapy with Dose Escalation to 54 Gy for Limited-Stage Small-Cell Lung Cancer

The combination of accelerated hyperfractionated thoracic radiotherapy (AHF-TRT) of 45 Gy and concurrent chemotherapy is the standard treatment for limited-stage small-cell lung cancer (LS-SCLC). However, the optimal dose and fractionation remain controversial. We herein report the results of a phase II study investigating the utility of dose escalation to 54 Gy on AHF-RT for LS-SCLC. We enrolled patients ≤80 years old with treatment-naïve confirmed LS-SCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The radiation dose was 54 Gy delivered in 36 fractions in 18 treatment days over 3.6 weeks. The chemotherapy regimens were PE (cisplatin and etoposide)- or CE (carboplatin and etoposide)-based. AHF-TRT was given in 2 phases: patients initially received 36 Gy to the gross tumor plus uninvolved mediastinal nodes, followed by a boost to the gross tumor of 18 Gy. All patients were treated with three-dimensional conformal radiation therapy with multiple fields to reduce the elevated dose volume to the surrounding tissues, such as the lungs and esophagus, as much as possible. All patients were evaluated for the overall survival (OS), progression-free survival (PFS), and non-hematological toxicity. Between 2013 and 2016, a total of 13 patients were enrolled in the present study. All the patients were assessable for the response and toxicity. The median age was 67 (range, 54-78) years old, and 9 patients were male, while 4 were female. Twelve patients had a ECOG performance status of 0. The numbers of patients with Stage IIA, IIB, IIIA, and IIIB disease were one, one, eight, and three, respectively. The median follow-up for all patients was 79 (range, 13-107) months, and that for surviving patients was 90 (range, 79-107) months. The patterns of failure were locoregional-only recurrence in 0% (0 patients), both locoregional and distant in 15.4% (2 patients), and distant-only in 30.8% (4 patients). Recurrence from the elective nodal irradiation area was seen in 0% (0 patients). The 1-, 3-, 5-, and 7-year OS rates were 100%, 76.9%, 53.9%, and 44.9%, respectively, and the median OS was 83.0 months. The 1-, 3-, 5-, and 7-year PFS rates were 76.9%, 53.9%, 53.9%, and 44.9%, respectively, and the median PFS was 83.0 months. No patient experienced a grade ≥3 non-hematological adverse effect, such as esophagitis or pneumonitis, during treatment or follow-up. Grade 2 pneumonitis was observed in 2 patients (15.4%), Grade 2 esophagitis was observed in 12 patients (92.3%), and Grade 2 esophageal pain was observed in 2 patients (15.4%). In this study, AHF-TRT of 54 Gy with concurrent PE- or CE-based regimens resulted in a good OS and PFS without increasing severe toxicity. Although this regimen needs to be evaluated in more patients to fully confirm its efficacy, these outcomes suggest that dose escalation to 54 Gy may be a promising radical treatment for LS-SCLC.

Application of a Contralateral Esophageal-Sparing Technique to Reduce Radiation Esophagitis in Limited-Stage Small Cell Lung Cancer Treated with Twice-Daily Radiotherapy and Concurrent Chemotherapy

Acute esophagitis (AE) is a common radiation-related toxicity after concurrent twice-daily hyperfractionated radiotherapy and chemotherapy in limited-stage small cell lung cancer (LS-SCLC) patients, which could limit dose-escalation of the target and make treatment postponed to decrease local tumor control. More esophageal protective techniques should be proposed to reduce radiation severe esophagitis of LS-SCLC patients. We retrospectively applied a contralateral esophagus sparing technique (CEST) in 20 unresectable LS-SCLC patients, who had gross tumor within 1 cm of the esophagus and received a total dose of 45 Gy of concurrent twice-daily radiation and standard chemotherapy regimen. The contralateral esophagus (CE) was contoured as an avoidance structure, and the feasibility of CEST on promoting a steep dose falloff beyond the target volume near esophagus was analyzed. The appropriate dose constraints of CE were also investigated. The AE events were recorded according to the RTOG acute toxicity grading system. We performed CEST in 20 LS-SCLC consecutive patients, among whom three patients experienced severe AE after concurrent chemoradiotherapy. Each treatment plan of eligible patients assured high radiation doses delivering, with the planning and gross tumor volume covered by 95% and 100% of the prescription dose. Among these patients, the median maximum esophagus dose declined from 47.9 Gy (range, 46.6-49.7 Gy) to 41.3 Gy (range, 35.9-48.2 Gy), as well as V30 and V36 of esophagus decreased from 9.22 Gy (range, 0.42-17.71 Gy) and 7.39 Gy (range, 0-16.19 Gy) to 2.40 Gy (range, 0-5.68 Gy) and 0.53 Gy (range, 0 -2.69 Gy) after CEST applying, respectively (all p<0.001). The CE's median maximum dose, V30, and V36 were 41.3 Gy, 2.13 cc, and 0.24 cc, respectively. By using proposed CE dose constraints of Dmax≤42 Gy, V30 ≤3.5 cc and V36 ≤0.5 cc, we confirmed the feasibility and efficacy of CEST to avoid exposing the esophagus cross-section to high prescription doses in LS-SCLC patients receiving twice-daily hyperfractionated IMRT and concurrent chemotherapy. These findings support the clinical practice of CEST in LS-SCLC patients, while more prospective and large-scale studies are warranted.

Proliferation Saturation Index to Simulate Adaptive Radiation Fractionation in HPV-Associated Oropharyngeal Cancer

In current clinical practice for fractionated radiotherapy (RT) patients receive a fixed fractionation protocol throughout radiation course. Radiation oncology has not yet moved toward adaptive fractionation to change RT fractionation based on individual patients' response dynamics. We have previously introduced a novel mathematical and imaging biomarker, proliferation saturation index (PSI), to simulate and evaluate tumor volume dynamics during therapy. Robust tumor volume reduction was associated with lower PSI, and PSI has been utilized to select fractionation schedules for the first mathematical model informed clinical trial. Here we simulate the possibility of adapting the selection of RT fractionation on a week-by-week basis by utilizing a dynamic weekly estimation of PSI. We generated a cohort of in silico patients by sampling from distributions of PSI, radiosensitivity, and growth rate parameters. These distributions were by pre-treatment and on-treatment tumor volume dynamics from a prospective clinical trial (NCT03656133), where 49 HPV+ OPC patients were treated with either 2 Gy daily fractions up to a total of 70 Gy if PS<0.75, or hyperfractionation at 1.2 Gy b.i.d. up to a total of 66 Gy for patients with PSI ≥ 0.75. We then simulated standard (2 Gy q.d.) and hyperfractionated (1.2 Gy b.i.d) for 1-8 weeks of RT to build a library of response dynamics for the different parameter combinations and treatment durations. This library was then used to estimate optimal adaptive fractionation schedules for the in silico patients that maximized tumor volume reduction and minimized total RT dose. We found that PSI evolved towards lower values (i.e., higher proliferative fractions) over the fractionation RT treatment course. For patients that began treatment with standard fractionation, no adaption was found to be superior to uniform fractionation. For selected patients who began treatment with hyperfractionation, however, the optimal fractionation schedule included a period of upfront hyperfractionated RT followed by a switch to standard fractionation at different times during their treatment course. The results of this study suggest that in addition to selecting the best initial fractionation schedule, a novel approach to personalize RT for OPC patients may include adapting the fractionation based on early treatment response dynamics. These results motivate validation in prospective clinical trials.

RADIOTHERAPY BED MODEL MULTIOBJECTIVE PARETO-INTERIOR DUAL-OPTIMIZATION FOR PROSTATE CANCER HYPERFRACTIONATED TREATMENT PLANNING AND ISODOSELINES INVENTION

In a previous publication, constrained evolutionary algorithms for IN-VITRO-BED-LQ model (Linear Quadratic Biological Effective Dose Model) in prostate cancer Hyperfractionation radiotherapy TPO were optimized with Pareto-Multiobjective (PMO) methods. This study improves the research with a further comparative IN-VIVO-BED-LQ model optimization followed by a precision-refinement with Interior Optimization (IO) methods. Complex software is developed based on hyperfractionation constraints, but with in vivo main parameters dataset, and IO programming. Results with software design algorithmic method take in handle subroutines functions and matrix-algebra method for setting constraints and 3D IO surfaces. Results with 3D Interior Optimization by using the Genetic Algorithms (GA) previous numbers show get very good precision with new-invention of isodoselines sharp determination. Solutions dataset is shortly compared with previous in vitro study. Findings prove comparative PMO 2D imaging charts and numerical values of PMO prostate cancer hyperfractionated TPO parameters. Applications for prostate tumors radiotherapy planning, especially with new Surfactal-Isodoselines, brain prostate metastases and stereotactic radiosurgery treatments are briefed.

Conventional radiation therapy with hyperfractionated radiation therapy in cancer hypopharynx - A prospective comparative study

Cancer treatment of the head and neck, the effectiveness of hyperfractionated radiation therapy (HFRT) has been revealed in recent randomized trials, mainly in their local control. As the hypopharynx is situated near the larynx, to achieve greater laryngeal preservation, local control of hypopharyngeal cancers should be achieved; it is very important to enhance the patient’s quality of life. In this study, hyperfractionated radiation therapy results were compared with conventional radiation therapy (CFRT) results.Patients with squamous cell cancer of hypopharynx (Stage II to IVA); were submitted with hyperfractionated (n = 34) or conventionally fractionated (n = 22) radiotherapy, with chemotherapy, between July 2018 to January 2020.In conventional radiotherapy, each patient received 2 Gy per fraction with a total dose of 66 Gy at over 6.3 weeks, along with concurrent cisplatin (30 mg/m 2) weekly. In hyperfractionated radiotherapy, each patient received 1.2 Gy per fraction two fractions per day six hours apart with a total dose of 72 Gy at over 6 weeks, along with concurrent cisplatin (30 mg/m 2) weekly. The endpoints were tumor response and toxicities.: Complete response rate in the HFRT group was 85.29% and that in the CFRT group was 68.18%. The most prevalent acute toxicities were skin, mucosal and dysphagia related. The acute skin toxicity was significantly higher in CFRT (54.55%) than in HFRT (44.12%).: This study suggests that for the treatment of locally advanced hypopharynx cancers, hyperfractionated radiation therapy with simultaneous chemotherapy can be a standard method of treatment and care.

Efficacy and safety of high dose twice-daily thoracic radiotherapy versus standard dose for limited stage small-cell lung cancer: A multicentre, open-label randomised, phase 3 trial.

8587 Background: We aimed to assess the efficacy and safety of high-dose, hyperfractionated thoracic radiotherapy of 54 Gy in 30 fractions compared with standard dose(45 Gy in 30 fractions) as a first-line treatment for LS-SCLC. Methods: The study was an open-label, randomised, phase 3 trial, done at 16 public hospitals in China.Key inclusion criteria were patients aged 18-70 years, with previously histologically or cytologically confirmed LS-SCLC, previously untreated or received 1-2 courses of intravenous cisplatin (75 mg/m²of body-surface area, on day 1 or divided into two days of each cycle) or carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle)and intravenous etoposide (100 mg/m²of body-surface area, on days 1-3 of each cycle), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.Eligible patients were randomly assigned (1:1) to receive receive volumetric-modulated arc radiotherapy (VMAT) of 45 Gy in 30 fractions or the simultaneous integrated boost VMAT (SIB-VMAT) of 54 Gy in 30 fractions to the primary lung tumour and lymph node metastases starting 0-42 days after the first chemotherapy course. Both groups of patients received thoracic radiotherapy twice per day and 10 fractions per week.Prophylactic cranial radiation (PCI, 25Gy in 10 fractions) was implemented to patients with responsive disease. The primary endpoint was overall survival. Safety was analysed in the as-treated population. This study is complete and registered with ClinicalTrials.gov,NCT03214003. Results: Between June 30, 2017, and April 6, 2021, 224 eligible patients were enrolled and randomly assigned to 54 Gy (n = 108) or 45 Gy (n = 116).Median follow-up for the primary analysis was 45 months (IQR 41-48). Median overall survival was significantly improved in the 54 Gy group (62.4 months ) compared with the 45 Gy group (43.1 months; p = 0.001). Median progression-free survival was significantly improved in the 54 Gy group (30.5 months) compared with the 45 Gy group (16.7 months; p = 0.044). The most common grade 3-4 adverse events were neutropenia (30 [28%] of 108 patients in the 54 Gy group vs 27 [23%] of 116 patients in the 45 Gy group), neutropenic infections (6 [6%] vs 2 [2%]), thrombocytopenia (13 [12%] vs 12 [10%]), anaemia (6 [6%] vs 4 [3%]), and oesophagitis (1 [1%] vs 3 [3%]). There were one treatment-related deaths in 54 Gy group (myocardial infarction). Conclusions: Compared with standard thoracic radiotherapy dose of 45 Gy, the high dose dose of 54 Gy improved overall survival and progression-free survival without increasing toxicities in patients with LS-SCLC, supporting twice-daily hyperfractionated thoracic radiotherapy of 54 Gy with concurrent chemotherapy is an alternative treatment option for LS-SCLC. Clinical trial information: NCT03214003 .

Application of a contralateral esophageal-sparing technique to reduce radiation esophagitis in limited-stage small cell lung cancer treated with twice-daily radiotherapy and concurrent chemotherapy.

e20644 Background: Acute esophagitis (AE) is a common radiation-related toxicity after concurrent twice-daily hyperfractionated radiotherapy and chemotherapy in limited-stage small cell lung cancer (LS-SCLC) patients, which could limit dose-escalation of the target and make treatment postponed to decrease local tumor control. More esophageal protective techniques should be proposed to reduce radiation severe esophagitis of LS-SCLC patients. Methods: We retrospectively applied a contralateral esophagus sparing technique (CEST) in 20 unresectable LS-SCLC patients, who had gross tumor within 1 cm of the esophagus and received a total dose of 45 Gy of concurrent twice-daily radiation and standard chemotherapy regimen. The contralateral esophagus (CE) was contoured as an avoidance structure, and the feasibility of CEST on promoting a steep dose falloff beyond the target volume near esophagus was analyzed. The appropriate dose constraints of CE were also investigated. The AE events were recorded according to the RTOG acute toxicity grading system. Results: We performed CEST in 20 LS-SCLC consecutive patients, among whom three patients experienced severe AE after concurrent chemoradiotherapy. Each treatment plan of eligible patients assured high radiation doses delivering, with the planning and gross tumor volume covered by 95% and 100% of the prescription dose. Among these patients, the median maximum esophagus dose declined from 47.9 Gy (range, 46.6-49.7 Gy) to 41.3 Gy (range, 35.9-48.2 Gy), as well as V30 and V36 of esophagus decreased from 9.22 Gy (range, 0.42-17.71 Gy) and 7.39 Gy (range, 0-16.19 Gy) to 2.40 Gy (range, 0-5.68 Gy) and 0.53 Gy (range, 0 -2.69 Gy) after CEST applying, respectively (all p &lt; 0.001). The CE’s median maximum dose, V30, and V36 were 41.3 Gy, 2.13 cc, and 0.24 cc, respectively. Conclusions: By using proposed CE dose constraints of Dmax≤42 Gy, V30 ≤3.5 cc and V36 ≤0.5 cc, we confirmed the feasibility and efficacy of CEST to avoid exposing the esophagus cross-section to high prescription doses in LS-SCLC patients receiving twice-daily hyperfractionated IMRT and concurrent chemotherapy. These findings support the clinical practice of CEST in LS-SCLC patients, while more prospective and large-scale studies are warranted.

Evaluation of Molecular-level Changes of Programmed Cell Death Ligand-1 after Radiation Therapy in a BALB/c CT26 Colorectal Mouse Tumor Model.

The effects of radiation therapy (RT) for cancer can be systemic and partially mediated by the immune system. However, radiation alone is unlikely to transform an immunosuppressive environment into an immunostimulatory one. Therefore, an effective combination of RT and immunotherapy may provide a new, more efficient treatment approach. Here, we investigated how the expression of programmed cell death-ligand 1 (PD-L1) in the tumor microenvironment varied in different RT regimens with the same biologically effective dose. In this study, female BALB/c mice inoculated with CT26 tumor cells were irradiated with 3 different RT regimens using the same BED of 40 gray (Gy). These included ablative RT (1*15 Gy), hypo-fractionated RT (2*10 Gy), and conventional (Hyper-fractionated) RT (10*3 Gy). PD-L1 expression was analyzed with immunohistochemical staining on days 2 and 20 and when the size of tumors had reached 2 cm2 after RT. All treated groups expressed PD-L1, but the group receiving single ablative high-dose RT showed higher expression compared to the other groups. No significant differences in PD-L1 expression were observed at different times in the same group. These findings showed that different regimens of RT have different effects on the TME, so a combination of RT and immune checkpoint blockade could be clinically used in cancer patients.

Prospective Evaluation of Limited-Stage Small Cell Lung Cancer Radiotherapy Fractionation Regimen Usage and Acute Toxicity in a Large Statewide Quality Collaborative

National guidelines on limited stage small cell lung cancer (LS-SCLC) treatment give preference to a hyperfractionated regimen of 45 Gy/30 fractions delivered twice-daily, however use of this regimen is uncommon compared to once-daily regimens. The purpose of this study was to characterize the LS-SCLC fractionation regimens used throughout a statewide collaborative, analyze patient and treatment factors associated with these regimens, and describe real-world acute toxicity profiles of once- and twice-daily RT regimens. Demographic, clinical, and treatment data along with physician toxicity and patient-reported outcomes were prospectively collected by 29 institutions within the [quality consortium] between 2012 and 2021 for patients with LS-SCLC. We modeled the influence of RT fractionation and other patient-level variables clustered by treatment site on the odds of a treatment break specifically due to toxicity with multilevel logistic regression. Common Terminology Criteria for Adverse Events, version 4.0, incident Grade 2 or worse toxicity was longitudinally compared between regimens. There were 78 patients (15.6% overall) treated with twice-daily RT and 421 patients treated with once-daily RT. Patients receiving twice-daily RT were more likely to be married/living with someone (65% vs 51%, p=0.019) and to have no major comorbidities (24% vs 10%, p=0.017). Once-daily RT fractionation toxicity peaked during RT and twice-daily toxicity peaked within 1 month after RT. After stratifying by treatment site and adjusting for patient-level variables, once-daily treated patients had a 4.11 (95% confidence interval 1.31-12.87) higher odds of treatment break specifically due to toxicity than twice-daily treated patients. Hyperfractionation for LS-SCLC remains infrequently prescribed despite the lack of evidence demonstrating superior efficacy or lower toxicity of once-daily RT. With peak acute toxicity after RT and lower likelihood of a treatment break with twice-daily fractionation in real-word practice, providers may start utilizing hyperfractionated RT more frequently.

867 Postoperative Metformin is Associated With Improved Survival of Glioblastoma Patients

INTRODUCTION: Metformin may improve clinical outcomes for glioblastoma (GBM) patients as metformin showed in vitro tumor suppressor functions, such as reducing the proliferation of GBM tumor-initiating cells by reversing Akt kinase activation. METHODS: A single-centre retrospective study of 288 patients who underwent biopsy or surgery for GBM between 2014-2018 was conducted. Postoperative metformin treatment includes patients who received metformin as part of an adjuvant therapy with temozolomide and/or hyper-fractionated radiotherapy. Kaplan-Meier curves and log-rank p test were used for univariate analysis. Cox-proportional hazards model was used to generate adjusted hazard ratios with 95% CI for multivariate analysis. RESULTS: Metformin use impacted OS of patients with MGMT-methylated (MGMTm+) tumors (n = 71 no metformin (Met-), n = 35 metformin use (Met +); median OS = 442 vs. 662 days; p = 0.13) but not in patients with unmethylated MGMT tumors (n = 104 Met-, n = 44 Met+; median OS = 279 vs 295 days; p = 0.674). Postoperative metformin treatment of MGMTm+ tumor patients improved OS when compared to no or only preoperative metformin treatment (n = 66 no or preoperative metformin use, n = 40 postoperative metformin use; median OS = 443 vs 595; p = 0.012). Further, postoperative metformin treatment of nondiabetic patients with MGMTm+ tumors improved OS (n = 70 Met-, n = 18 postoperative Met+; median OS = 422 vs 582; p = 0.017). A multivariable model considering age, Karnofsky Performance Status (KPS), and extent of resection (EOR), demonstrated that postoperative metformin improves OS of MGMTm+ patients (aHR 0.500, 0.287-0.872, p = 0.015). Comparing postoperative with no or preoperative use of metformin produced a similar effect on OS (aHR 0.411, 0.177-0.954, p = 0.038). Postoperative treatment of nondiabetic patients with MGMTm+ tumors demonstrated improved OS (aHR 0.367, 0.156-0.864, p = 0.022). CONCLUSIONS: Postoperative metformin treatment of patients with MGMTm+ tumors is associated with improved OS, irrespective of age, diabetic status, KPS, or EOR.

Hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial

Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.

HPV and RAD51 as Prognostic Factors for Survival in Inoperable Oral and Oropharyngeal Cancer in Patients Unfit for Chemotherapy Treated with Hyperfractionated Radiotherapy.

The incidence of advanced oral cavity and oropharyngeal cancers is generally high. Treatment outcomes for patients, especially those unfit for comprehensive cancer treatment, are unsatisfactory. Therefore, the search for factors to predict response to treatment and increase overall survival is underway. This study aimed to analyze the presence of 32 HPV genotypes in tumor samples of 34 patients and the effect of HPV status and RAD51 on overall survival. Tumor samples of 34 patients with locally advanced oropharyngeal or oral cavity cancer treated with accelerated radiotherapy in monotherapy were analyzed using reverse hybridization and immunohistochemistry for the presence of HPV and RAD51. Its effect on overall survival was examined. Only two types of HPV were identified-HPV 16 (dominant) and HPV 66 (two samples). The HPV positivity was associated with a borderline insignificant improvement in 2-year (p = 0.083), 5-year (p = 0.159), and overall survival (p = 0.083). Similarly, the RAD51 overexpression was associated with borderline insignificant improvement in 2-year (p = 0.083) and 5-year (p = 0.159) survival. We found no statistically significant differences but detected trends toward improvement in the survival of HPV-positive and RAD51 overexpressing patients unfit for surgical treatment or chemotherapy treated with hyperfractionated radiotherapy. The trends, however, indicate that in a larger group of patients, the effects of these two parameters would likely be statistically significant.

Antineoplastic Activity of Pazopanib in Anaplastic Thyroid Cancer in Primary Culture.

Anaplastic thyroid cancer (ATC) is a rare and rapidly fatal human cancer. Its usual treatment includes the combination of surgery, external hyperfractionated radiation therapy, and chemotherapy. These treatments permit achieving about 6-10 months of median survival. For this reason, it is challenging to predict the ATC patient clinical therapy responsiveness. Pazopanib is a multitarget tyrosine kinase inhibitor of VEGF receptors, PDGF, and c-Kit. Until now, the effect of pazopanib in primary human ATC cells (pATC) has not been reported in the literature. The aim of our study was to evaluate in vitro the antineoplastic effect of pazopanib in pATC. Surgical thyroidal tissues were collected from five patients with ATC, from thyroid biopsy at the moment of first surgical operation. An inhibition of proliferation, migration, and invasion, and an increase in apoptosis were demonstrated upon treating pATC cells with pazopanib (p < 0.05). Moreover, pazopanib was able to significantly decrease the VEGF expression in pATC cells (p < 0.05). To conclude, in this study, we demonstrate the antineoplastic activity of the antiangiogenic inhibitor, pazopanib, in human pATC in vitro.