International Journal of Radiation Oncology Biology Physics最新文献

{"title":"MORF4L1-Mediated DNA Damage Repair Modulates cGAS-STING Activation and Radiosensitivity in Hepatocellular Carcinoma","authors":"S. Wang ,&nbsp;W. Hong ,&nbsp;Y. Huang ,&nbsp;C. Gao ,&nbsp;A. Ke ,&nbsp;Z. Zeng ,&nbsp;S. Du","doi":"10.1016/j.ijrobp.2024.07.037","DOIUrl":"10.1016/j.ijrobp.2024.07.037","url":null,"abstract":"<div><h3>Purpose/Objective(s)</h3><div>Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with poor prognosis. Radiotherapy (RT) is one of the main treatments for patients with unresectable HCC, but its efficacy has been limited due to inherent or acquired radiation resistance. However, the regulatory mechanisms of radiation resistance in HCC remain unclear.</div></div><div><h3>Materials/Methods</h3><div>Key DDR genes in HCC were identified by single-cell RNA sequencing (GSE149614). In vitro experiments confirmed that the expression level of MORF4L1 regulates DNA damage repair and susceptibility to radiotherapy of HCC cells. Immunoprecipitation-mass spectrometry was used to explore the core mechanism of MORF4L1 mediating DNA damage repair. Mechanisms of MORF4L1 antagonist combined with radiotherapy to enhance anti-tumor immune response was demonstrated by in vitro cell co-culture model, small molecule inhibitor and genetically engineered mice.</div></div><div><h3>Results</h3><div>In this study, MORF4L1 was identified as a key DDR gene in HCC by single-cell RNA sequencing (GSE149614). High expression of MORF4L1 mediates poor prognosis and poor RT efficacy in patients with HCC. The expression level of MORF4L1 regulates DNA damage repair and susceptibility to radiation therapy in liver cancer cells. Mechanistically, MORF4L1 mediates acetylation of histone H3 at lysine 4 to promote DNA damage repair. Knocking out MORF4L1 or inhibiting histone acetylation reduced recruitment of PALB2, BRCA2, and RAD51 at sites of DNA damage. Using in vitro cell co-culture models and genetically engineered mice, we demonstrated that the FDA-approved drug argatroban (MORF4L1 antagonist) combined with RT can enhance the anti-tumor immune response by activating the cGAS-STING signaling pathway.</div></div><div><h3>Conclusion</h3><div>This work highlights the mechanism of MORF4L1 as a key gene in HCC DNA damage repair. RT combined with argatroban enhances anti-tumor immune response by activating cGAS-STING signaling pathway, providing new insights for improving the efficacy of RT for HCC.</div></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":"120 2","pages":"Page S29"},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP15 and Radiation-Induced DNA Damage Repair of Intestinal Epithelial Cells by Deubiquitinating and Stabilizing ATM","authors":"R. Zhu ,&nbsp;S. Cai ,&nbsp;Y. Tian","doi":"10.1016/j.ijrobp.2024.07.042","DOIUrl":"10.1016/j.ijrobp.2024.07.042","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Purpose/Objective(s)&lt;/h3&gt;&lt;div&gt;The intestine is vulnerable to structural and functional damage caused by exposure to radiation. Unfortunately, there is currently no effective prophylactic or therapeutic strategy available to mitigate radiation-induced intestinal injury (RIII). Deubiquitinating enzymes (DUBs) play a crucial role in repairing DNA breaks. Therefore, we conducted a new study on the pathogenesis of RIII by examining the role of DUBs, in order to identify potential directions for therapeutic or preventive measures in this area.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Materials/Methods&lt;/h3&gt;&lt;div&gt;The effects of 14 Gy whole abdominal irradiation (WAI) on DUB levels in the intestine of C57BL/6J mice were investigated by RNA-seq analysis. In vivo and in vitro experiments were conducted using the ubiquitin-specific proteases 15 (USP15) inhibitor (USP15-IN-1). The impact of USP15 on the radiosensitization of HIEC-6 cells was observed. The survival and body weight of mice in each irradiated group were recorded, and the severity of radiation-induced intestinal injury (RIII) was evaluated through HE staining, immunohistochemistry (IHC), and the TUNEL method. USP15-bound proteins were identified and validated through mass spectrometry analysis. The role of USP15 in ataxia-telangiectasia mutated (ATM) deubiquitination and stability was determined by constructing a USP15 mutant (C298A). Finally, the potential reversal of USP15 knockdown’s promotional effects on radiosensitizing effect in HIEC-6 cells by ATM was investigated.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;USP15 is one of the top 20 highly expressed genes in the intestinal tissue of mice after exposure to 14Gy of WAI. Inhibition of USP15 resulted in increased radiosensitivity of HIEC-6 cells, as evidenced by a decrease in colony-forming ability and an increase in the formation of micronuclei and apoptotic cells, as well as an increase in 8-OHdG fluorescence intensity. Comet assay and γ-H2AX staining revealed more DNA damage in irradiated HIEC-6 cells treated with USP15-IN-1. In vivo, USP15 was found to modulate apoptosis and DNA damage in the small intestine of mice exposed to WBI. Mass spectrometry analysis showed that USP15 interacts with the protein kinase ATM, a key regulator of DNA double-strand break (DSB) signaling and stress response. By creating a mutant form of USP15(C298A), it was discovered that USP15 directly interacts with ATM, independent of its DUB activity, and can regulate the stability of ATM protein. Furthermore, USP15 was found to specifically disassemble K48-linked polyubiquitination of ATM but had no significant effect on monoubiquitination or other types of polyubiquitination. The radiosensitizing effect produced by knockdown of USP15 in HIEC-6 cells can be reversed by ATM.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Our findings demonstrate that USP15 plays a crucial role in repairing radiation damage in intestinal epithelial cells by counteracting ATM ubiquitination and degradation, w","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":"120 2","pages":"Page S31"},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Examining the Impact of Combined P53 Status and PD-L1 Expression on Vulvar Cancer Outcomes","authors":"B. Elgohari ,&nbsp;P.P. Patwardhan ,&nbsp;R. Bhargava ,&nbsp;P. Sukumvanich ,&nbsp;M. Courtney-Brooks ,&nbsp;M. Boisen ,&nbsp;J.L. Berger ,&nbsp;S. Taylor ,&nbsp;A. Olawaiye ,&nbsp;J. Lesnock ,&nbsp;R.P. Edwards ,&nbsp;T.R. Soong ,&nbsp;J.A.A. Vargo IV","doi":"10.1016/j.ijrobp.2024.07.043","DOIUrl":"10.1016/j.ijrobp.2024.07.043","url":null,"abstract":"<div><h3>Purpose/Objective(s)</h3><div>Vulvar cancer (VC) has a heterogeneous microenvironment with complex cellular and molecular interactions, which poses a challenge to predict clinical outcomes. VC is commonly known to associated with 2 pathways: HPV dependent, and independent pathway. Little is known about the combined impact of p53 and PD-L1 expression on VC prognosis. We aimed to examine the combined impact of p53 status and PD-L1 expression on treatment outcomes for vulvar cancer.</div></div><div><h3>Materials/Methods</h3><div>A single institutional retrospective study of 90 VC patients treated from 2010 to 2021 was conducted. P53 status was evaluated for wild-type (p53wt) versus aberrant (p53a) by immunohistochemical (IHC) expression. Positive PD-L1 status (PD-L1+) was defined as a Combined Positive score of ≥ 1. The VCs were classified into a 4-category scheme based on PD-L1 and p53 status (PD-L1/p53): PD-L1+/p53a; PD-L1+/p53wt; PD-L1-/p53a; and PD-L1-/p53wt. Associations with outcomes including overall survival (OS), disease-free survival (DFS), local control (LC), and regional control (RC) were assessed via log-rank tests and multivariable Cox regression analyses.</div></div><div><h3>Results</h3><div>The median age was 72 years (IOR = 62–80 years). Most cases (<em>n</em> = 88) were squamous cell carcinoma, 48% of FIGO I-II, 35% were positive for p16, and close to half (44%) were PD-L1+/p53a (see Table 1). Most (74%) received as initial treatment surgery± postoperative radio± chemotherapy (S+POT), versus 26% received upfront definitive chemoradiotherapy (DCRT). Median follow-up: 38 months (IQR = 17–66). The p53a VC showed a statistically significantly worse 5-yr OS (45%, 95 CI = 27–63) than the p53wt VCs (85%, 95 CI = 72–97, <em>P</em> = 0.01) as with DFS, LC, and RC. We observed a significant difference in 5yr OS when patients were stratified by initial treatments received (Table 1) and with 5-yr DFS, and RC as outcomes of measures. On multivariable analysis, PD-L1-/p53a status was associated with worse OS (HR = 3.6, 95% CI = 1.1–11.3) after controlling for p16 status, age, FIGO stage, and other clinicopathologic factors. Other PD-L1/p53 status groups were not found to be independent predictors of clinical outcomes.</div></div><div><h3>Conclusion</h3><div>These results suggest that PD-L1-/p53a VCs as a subtype are prognostic for worse OS. This classification suggests the complex interaction between p53 and PD-L1 and the potential prognostic significance for oncological outcomes. The PD-L1/p53 classification could help risk-stratify VCs in routine practice and potentially guide personalized therapy.</div></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":"120 2","pages":"Pages S31-S32"},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Initial Clinical Experience of Cherenkov Imaging in Sub-Total Total Skin Electron Therapy Identifies Opportunities to Improve Daily Set-Up QA","authors":"B. Byrd ,&nbsp;Y. Zhu ,&nbsp;D.A. Alexander ,&nbsp;M. Chelius ,&nbsp;G.M. Freedman ,&nbsp;M.J. LaRiviere ,&nbsp;J.P. Plastaras ,&nbsp;T. Zhu","doi":"10.1016/j.ijrobp.2024.07.019","DOIUrl":"10.1016/j.ijrobp.2024.07.019","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Purpose/Objective(s)&lt;/h3&gt;&lt;div&gt;Total skin electron therapy (TSET) is a prevalent treatment modality for patients with cutaneous T-cell lymphomas. However, patient-specific QA measures for these TSET patients are lacking. Unlike isocentric treatments, there are no prior CT scans to utilize for planning, nor are there automated motion-management systems in place to ensure consistent and accurate patient positioning from day-to-day and while the patient is standing for treatment. To add additional variability, sub-total skin electron therapy patient treatments are commonly performed without treatment planning systems available to simulate and verify field edges.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Materials/Methods&lt;/h3&gt;&lt;div&gt;To address this unmet need for patient-specific QA, we deployed a clinical Cherenkov imaging system which utilizes three cameras to capture the Cherenkov emission on the patient’s skin surface from one frontal and two lateral directions. There were 52 TSET subjects enrolled under an ongoing IRB-approved clinical Cherenkov imaging study. Amongst the 52 enrolled subjects, 7 patients were withdrawn, 7 subjects were repeat study enrollments, imaged in two separate TSET study cases, and 24 of 52 (46%) treatments were sub-total skin electron therapy cases. All 52 TSET Cherenkov study cases were manually examined to identify potential clinically relevant differences between the planned vs. observed treatment fields within the standard Stanford 6-position treatment scheme.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Among the 52 Cherenkov TSET cases examined, two cases exhibited reduced dose to the upper extremities due to partial blocking, and one case saw increased dose in the subject’s left arm due to patient movement during treatment delivery. In four cases involving head blocking in the posteroanterior (PA) position, the subjects’ forearms were suboptimally aligned, parallel to the beam, rather than perpendicular to it. These specific observations were corroborated by Monte Carlo simulations, which also found reduced dose in a patient’s forearm region after accumulating skin dose from all 6 positions. Lastly, in one subject, Cherenkov imaging detected suboptimal hand positioning in the right anterior oblique (RAO) position, which was subsequently corrected for in the left anterior oblique (LAO) position. Notably, all instances of dose discrepancies or suboptimal patient positions occurred in cases with partial body blocking planned as part of the treatment, i.e. sub-total skin electron therapy.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;When blocking is clinically indicated, modifications to the standard Stanford 6-position treatment are often required. As shown in this analysis, these modifications may increase the difference in planned vs. delivered dose to specific blocked or unblocked anatomic regions. To address these challenges, Cherenkov imaging represents a highly useful record-and-verify tool for ensuring proper patient positioning and field","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":"120 2","pages":"Page S20"},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Honorary Member Thevenot Tribute","authors":"","doi":"10.1016/j.ijrobp.2024.06.026","DOIUrl":"10.1016/j.ijrobp.2024.06.026","url":null,"abstract":"","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":"120 2","pages":"Pages A19-A20"},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Opioid Therapy vs. Multimodal Analgesia in Head and Neck Cancer (OPTIMAL-HN): Results of a Randomized Clinical Trial","authors":"S. Zayed ,&nbsp;P. Lang ,&nbsp;N.E. Read ,&nbsp;R.J.M. Correa ,&nbsp;A. Mutsaers ,&nbsp;C.D. Goodman ,&nbsp;K. D’Angelo ,&nbsp;K. Kieraszewicz ,&nbsp;D. Vanwynsberghe ,&nbsp;A. Kingsbury-Paul ,&nbsp;K. Crewdson ,&nbsp;C. Carreau ,&nbsp;E. Winquist ,&nbsp;S. Kuruvilla ,&nbsp;P. Stewart ,&nbsp;D. Moulin ,&nbsp;A. Warner ,&nbsp;D.A. Palma","doi":"10.1016/j.ijrobp.2024.07.053","DOIUrl":"10.1016/j.ijrobp.2024.07.053","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Purpose/Objective(s)&lt;/h3&gt;&lt;div&gt;Radiation-induced mucositis (RIM) pain confers substantial morbidity for head and neck cancer (HNC) patients undergoing radiotherapy (RT) or chemoradiotherapy (CRT). With no established standard treatment, OPTIMAL-HN aimed to demonstrate the non-inferiority of multimodal analgesia (MMA; analgesic medications with different mechanisms of action) to the institutional standard of opioid analgesia alone.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Materials/Methods&lt;/h3&gt;&lt;div&gt;OPTIMAL-HN (NCT04221165) was an open label, single-institution, non-inferiority, randomized clinical trial. HNC patients receiving curative-intent RT/CRT and experiencing moderate 4 of 10 RIM pain were randomized 1:1, stratified by RT vs. CRT, to opioids alone per institutional standard or MMA (Pregabalin, Acetaminophen, Naproxen, and opioids if required). The primary endpoint was mean pain score (range = 0-10) during the last week of RT. Secondary endpoints included mean weekly opioid use, duration of opioid requirement, mean daily pain score, quality of life, hospitalizations for analgesic medication-related complications, time to feeding tube insertion, weight loss, toxicity, RT interruptions, and death. Assuming a non-inferiority margin of 1 point, a standard deviation of 1.5 in both arms (80% power, 1-sided alpha 0.05, dropout rate 6%), 62 patients were required. All analyses were pre-specified, including testing for superiority if non-inferiority was demonstrated, and intention-to-treat.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Forty-nine patients were enrolled, 25 in the opioid analgesia alone arm and 24 in the MMA arm. The trial was prematurely closed due to slow accrual. Baseline characteristics were well-balanced between arms; median age was 61 (IQR = 53-70) years; 36 male (73.5%) and 13 female (26.5%); baseline median pain score was 5 (IQR = 4-6) in the opioid arm and 4 (IQR = 4-6) in the MMA arm (&lt;em&gt;P&lt;/em&gt; = 0.161). Median follow-up was 4.24 (IQR = 3.75-4.73) months. The primary endpoint, mean pain score during the last 7 days of RT, was 5.10 (95% CI = 4.11-6.09) in the opioid arm and 4.85 (95% CI = 3.81-5.90) in the MMA arm (non-inferiority &lt;em&gt;P&lt;/em&gt; = 0.039, superiority &lt;em&gt;P&lt;/em&gt; = 0.724). Analyzing all pain scores from enrollment to 6 weeks post-RT using linear mixed models, MMA demonstrated significantly lower pain scores compared to opioids alone (non-inferiority &lt;em&gt;P&lt;/em&gt; = 0.002, superiority &lt;em&gt;P&lt;/em&gt; &lt; 0.001). Median weekly opioid use was numerically higher in the opioid arm (99.2 mg oral morphine equivalent dose [OMED], IQR = 16.3-173.1) compared to the MMA arm (50.5 mg OMED; IQR = 8.4-126.3), although nonsignificant (&lt;em&gt;P&lt;/em&gt; = 0.435). One patient in the MMA arm was admitted with grade 3 acute kidney injury, possibly related to the analgesic regimen. There was no grade ≥ 3 toxicity in the opioid arm. Arms were similar for all other secondary endpoints.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;MMA demonstrates non-inferiority to opioid anal","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":"120 2","pages":"Pages S36-S37"},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating Toxicity and Interaction Outcomes of Systemic Therapy and Stereotactic Ablative Radiotherapy for Oligometastatic Disease: A Secondary Analysis of the Phase II SABR-5 Trial","authors":"A. Kooyman ,&nbsp;J.S. Chang ,&nbsp;M. Liu ,&nbsp;W. Jiang ,&nbsp;A. Bergman ,&nbsp;D. Schellenberg ,&nbsp;B. Mou ,&nbsp;A.S. Alexander ,&nbsp;H. Carolan ,&nbsp;F. Hsu ,&nbsp;S. Atrchian ,&nbsp;E.K. Chan ,&nbsp;T. Berrang ,&nbsp;N. Chng ,&nbsp;Q. Matthews ,&nbsp;H.H. Pai ,&nbsp;B. Valev ,&nbsp;S. Tyldesley ,&nbsp;R.A. Olson ,&nbsp;S. Baker","doi":"10.1016/j.ijrobp.2024.07.031","DOIUrl":"10.1016/j.ijrobp.2024.07.031","url":null,"abstract":"<div><h3>Purpose/Objective(s)</h3><div>While SABR is known for its overall low toxicity and safety, there remains a research gap regarding its combined use with specific systemic therapies. This study aims to evaluate the toxicity of SABR in combination with various systemic therapies. The hypothesis is that certain systemic therapies would significantly increase the risk of Grade 2+ and Grade 3+ radiation therapy-related toxicities when used concurrently with Stereotactic Ablative Radiotherapy (SABR).</div></div><div><h3>Materials/Methods</h3><div>A secondary analysis of the SABR-5 trial compared grade 2+ and 3+ toxicities associated with SABR until the last follow-up in patients receiving high-risk or non-high-risk systemic therapy at intervals of 3 months, 2 weeks, 1 week, and concurrently with SABR. High-risk systemic therapy was a priori defined, based on previous literature, as drugs that, when given close to SABR, may increase treatment toxicity. This category encompasses cytotoxic chemotherapy drugs, multi-targeted tyrosine kinase inhibitors, cyclin-dependent kinase 4/6 inhibitors, epidermal growth factor receptor inhibitors, anti-vascular endothelial growth factor agents, and anti-cytotoxic T-lymphocyte-associated protein 4 agents.</div></div><div><h3>Results</h3><div>Among the 381 patients, the actuarial rates of grade 2+ and 3+ toxic effects were as follows: for patients not on systemic therapy 3 months prior to SABR (<em>n</em> = 202), the rates were 17.3% and 3.5%, respectively; for patients on non-high-risk systemic therapy concurrent with SABR (<em>n</em> = 102), the rates were 18.6% and 3.9%, respectively; and for patients on high-risk systemic therapy concurrent with SABR (<em>n</em> = 5), the rates were notably higher at 60% and 40%, respectively. On multivariable analysis, concurrent use of high-risk systemic therapy was associated with a higher risk of grade 2+ (OR = 7.15, <em>P</em> = 0.043) or 3+ toxic effects (OR = 13.9, <em>P</em> = 0.015). Significance was not observed when high-risk drugs were used only within 1 week, 2 weeks, or 3 months of SABR, nor with the use of any non-high-risk drugs. A second adverse factor included increased tumor diameter (per 1 cm increment; G2+ OR = 1.25, <em>P</em> &lt; 0.001; G3+ OR = 1.27, <em>P</em> = 0.015).</div></div><div><h3>Conclusion</h3><div>High-risk drugs have demonstrated a potential of increased SABR-related toxicity, warranting caution in their concurrent use with SABR. In contrast, the combination of non-high-risk drugs with SABR may be safe. Ongoing efforts are essential to identify potential risks and uncertainties associated with this therapeutic combination.</div></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":"120 2","pages":"Page S26"},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety Profile of Durvalumab (D) as Consolidation Treatment (tx) in Limited-Stage Small-Cell Lung Cancer (LS-SCLC) in ADRIATIC: Focus on Pneumonitis and Immune-Mediated Adverse Events (imAEs)","authors":"P. Iyengar ,&nbsp;Y. Cheng ,&nbsp;D. Spigel ,&nbsp;B.C. Cho ,&nbsp;K. Laktionov ,&nbsp;Y. Chen ,&nbsp;K.H. Lee ,&nbsp;E. Buchmeier ,&nbsp;N. Villanueva Palicio ,&nbsp;I. Okamoto ,&nbsp;A. Badzio ,&nbsp;A. SHI ,&nbsp;S. Lu ,&nbsp;M. Özgüroğlu ,&nbsp;Y. Ohe ,&nbsp;R. Bernabe ,&nbsp;B. Gill ,&nbsp;P. Chugh ,&nbsp;H. Gowda ,&nbsp;S. Senan","doi":"10.1016/j.ijrobp.2024.08.024","DOIUrl":"10.1016/j.ijrobp.2024.08.024","url":null,"abstract":"<div><h3>Purpose/Objective(s)</h3><div>In the phase 3 ADRIATIC study (NCT03703297) in patients (pts) with LS-SCLC without progression after concurrent chemoradiotherapy (cCRT), D as consolidation tx significantly improved OS and PFS vs placebo (P) at the first planned interim analysis. D was well tolerated and AEs were consistent with the known safety profile. Here we present pneumonitis/radiation pneumonitis and imAEs.</div></div><div><h3>Materials/Methods</h3><div>530 eligible pts with stage I–III LS-SCLC (stage I/II inoperable), WHO PS 0/1, and no progression after cCRT, were randomized 1–42 days after cCRT to D 1500 mg or P every 4 weeks until investigator-determined progression or intolerable toxicity, or for a maximum of 24 months. Safety was a secondary endpoint. Given the similar clinical presentation of pneumonitis resulting from prior RT (radiation pneumonitis) or immunotherapy (immune-mediated pneumonitis), these events were analyzed as a grouped term to better estimate their frequency. imAEs were also assessed.</div></div><div><h3>Results</h3><div>262 pts received D and 265 received P. Pneumonitis/radiation pneumonitis (preferred terms of immune-mediated lung disease, interstitial lung disease, pneumonitis, radiation fibrosis–lung, and radiation pneumonitis) occurred in 38% (n=100) vs 30% (n=80) of pts in the D vs P arm (maximum grade 3/4 3% vs 3%; grade 5 0.4% vs 0%; leading to tx discontinuation 9% vs 3%). Median time from first study drug dose to onset (mTTO) of pneumonitis/radiation pneumonitis was 56 days (range 1–594) vs 56 days (2–228) in the D vs P arm; 40/100 events in the D arm and 23/80 in the P arm had resolved at data cutoff (Jan 15, 2024). imAEs occurred in 32% vs 10% of pts in the D vs P arm (maximum grade 3/4 5% vs 2%; grade 5 0.4% vs 0%; leading to tx discontinuation 7% vs 3%). 14% vs 6% of pts in the D vs P arms received high-dose steroids and 1% vs 0.4% received immunosuppressants to manage imAEs. The table shows mTTO, resolution, and median time to resolution (mTTR) for the most common imAEs.</div></div><div><h3>Conclusion</h3><div>In ADRIATIC, pneumonitis/radiation pneumonitis was common in both arms in this population who had received prior RT, and imAEs were as expected in the D arm; these events were mainly low grade and led to low rates of tx discontinuation, supporting the favorable benefit-risk profile for consolidation D after cCRT in LS-SCLC.</div></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":"120 2","pages":"Pages S8-S9"},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase II Trial of Proton Re-Irradiation+/-Chemotherapy in Previously Irradiated Recurrent Head/Neck Cancer","authors":"N.Y. Lee ,&nbsp;N.S. Kalman ,&nbsp;C.A. Barker ,&nbsp;C. White ,&nbsp;Z. Zhang ,&nbsp;D. Gelblum ,&nbsp;Y. Yu ,&nbsp;L. Chen ,&nbsp;S. McBride ,&nbsp;N. Riaz ,&nbsp;A. Shamseddine ,&nbsp;L. Michel ,&nbsp;T. Hung ,&nbsp;D.G. Pfister ,&nbsp;B. Singh ,&nbsp;I. Ganly ,&nbsp;J.O. Boyle ,&nbsp;R.J. Wong ,&nbsp;P.B. Romesser ,&nbsp;E. Sherman","doi":"10.1016/j.ijrobp.2024.07.051","DOIUrl":"10.1016/j.ijrobp.2024.07.051","url":null,"abstract":"<div><h3>Purpose/Objective(s)</h3><div>To report the results of a multi-center phase II trial of using proton re-irradiation (re-RT) for previously irradiated recurrent head/neck cancer (HNC).</div></div><div><h3>Materials/Methods</h3><div>Recurrent HNC patients who received &gt;/= 40 Gy of prior head/neck radiation were enrolled. Patients received fractionated re-RT (F-Re-RT to 70 Gy) or QUAD Shot re-RT (QS-Re-RT, 4 cycles to 59.2 Gy) at physician discretion. The primary endpoints (Clopper-Pearson Confidence Intervals method) were to determine the 12-months, 6-months locoregional recurrence-free (LRRF) rates for F-Re-RT and QS-Re-RT, respectively. Secondary endpoints were to determine: overall survival (OS), progression-free survival (PFS) [both estimated using the Kaplan-Meier method]; distant metastasis (DM), locoregional recurrence (LRR) rates [both calculated from using the Cumulative Incidence Function with death as a competing event]. Patient reported outcomes (PROs) included EORTC QLQ-HN35, PRO-CTCAE, Skindex-16, OMWQ-HM mucositis, EQ-5D. Median follow-up was calculated using the Reverse Kaplan-Meier method.</div></div><div><h3>Results</h3><div>From July 2017 to November 2022, 88 patients were enrolled (85 analyzable): F-Re-RT (<em>n</em> = 57) versus QS-Re-RT (<em>n</em> = 28). F-Re-RT patients were young with better performance status versus QS-Re-RT patients. Median follow-up was 35 months (all patients); F-Re-RT (38 months); QS-Re-RT (23 months). The 1-year LRRF rate for F-Re-RT was 71% (90% CI = 59%, 81%); 6-month LRRF rate for QS-Re-RT was 76% (90% CI = 58%, 89%) [See table for treatment factors, other endpoints] 36% of the patients had acute grade 3-4 toxicities, most notably dermatitis, dysphagia, dysgeusia. Late grade 3 complications were 20% (see the Table below). Nine patients had grade 4 and 3 had grade 5 complications. The Baseline, 1-year post re-RT mean score of EORTC QLQ-HN35 for F-Re-RT versus QS-Re-RT were 31.05 to 39.09 versus 35.43 to 14.85. Other PROs will be presented at the meeting.</div></div><div><h3>Conclusion</h3><div>In this largest and first multi-center phase II trial for recurrent HNC patients, proton therapy achieved remarkable locoregional control and survival. Although long-term survivors (&gt; 5 years) were observed which compares very favorably to other treatment modalities, especially when multiple therapies were done prior to re-RT with proton, these patients remain at risk for late complications.</div></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":"120 2","pages":"Pages S35-S36"},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Longitudinal Study to Correlate Neurocognitive Changes of IDH-Mutant and IDH-Wildtype Glioma Patients after Chemoradiotherapy with Changes on Resting-State MRI","authors":"Z. Liu ,&nbsp;T. Mitchell ,&nbsp;C. Luo ,&nbsp;J.S. Shimony ,&nbsp;K.Y. Park ,&nbsp;R. Fucetola ,&nbsp;S.M. Perkins ,&nbsp;E.C. Leuthardt ,&nbsp;A. Snyder ,&nbsp;T. Zhu ,&nbsp;J. Huang","doi":"10.1016/j.ijrobp.2024.07.059","DOIUrl":"10.1016/j.ijrobp.2024.07.059","url":null,"abstract":"<div><h3>Purpose/Objective(s)</h3><div>This prospective observational study investigates mechanisms behind neurocognitive function (NCF) decline after partial-brain irradiation in malignant glioma patients. We aim to use resting-state functional MRI (RS-fMRI) to identify the dominant network-level disturbances post-radiation therapy (RT) that correlate with NCF changes.</div></div><div><h3>Materials/Methods</h3><div>Adult patients with IDH-wildtype or IDH-mutant gliomas underwent NCF test using the NIH Toolbox Cognitive Function Battery at baseline and 6 months post RT. The battery includes fluid cognition tests: dimension change card sort test (executive function), flanker test (attention), picture sequence test (episodic memory), list sorting test (working memory), and pattern comparison test (processing speed). The five test scores were then combined into an age-normalized composite score, from which the percent change of composite (PCC) was calculated relative to the baseline. To determine a potential correlation between NCF and changes in brain functional connectivity (FC), we used seed-based FC analysis from a 12-minute RS-fMRI scan. A split-sample approach was used for analysis, with a 26-patient training set and a 6-patient validation set, iterated 200 times. Within each run, connectivity-regression analysis within the training set was first used to identify which intra- or inter-network FC change was most significantly associated with PCC, and a linear regression was used to predict FC change of the selected networks using the validation set. Permutation test was used to evaluate the significance of network selection, and R² value was used to evaluate the predictive performance.</div></div><div><h3>Results</h3><div>From September 2020 to December 2023, there were 43 patients who had baseline data, while 32 patients completed 6-month follow-ups and were evaluable. The mean NCF composite changed from 88.8 (±16.2) at baseline to 91.1 (±19.4) at 6 months. The mean PCC was 2.9 (±13.7), including 12 patients with negative PCC (Decline cohort) and 20 patients with positive PCC (Non-decline cohort). The clinical, treatment, and dosimetric characteristics between two cohorts were not significantly different among 24 variables examined. The mean R2 was 0.36 (±0.27). The most significant correlations with PCC were consistently observed in the inter-network FC changes between Default Mode Network to Medial Temporal Lobe (DMN-MTL, <em>P</em> = 0.005) and Parietal Memory Network to MTL (PMN-MTL, <em>P</em> = 0.02). Sensitivity analyses using only FC maps from the contra-lateral side of the tumor confirmed the same finding.</div></div><div><h3>Conclusion</h3><div>RS-fMRI changes post RT correlated with NCF decline, suggesting its potential as an imaging biomarker. Specifically, disruption of inter-network FC between DMN-MTL and PMN-MTL may be key mechanism underlying RT-induced NCF decline, warranting further investigation.</div></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":"120 2","pages":"Page S40"},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142359157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}