Lee SF, Wong HCY, Tse SSW
… +19 more, Choi JI, Bonomo P, Chan RJ, Jefford M, Corbin KS, Alcorn SR, Hijal T, Cao JQ, Chow E, Kwan JYY, Hirakawa S, Oyoshi H, Tomizawa K, Zenda S, Salako O, Ghosh-Laskar S, Nejjar I, Wolf JR, van den Hurk C
Int J Radiat Oncol Biol Phys
· 2026 Jun · PMID 42235693
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PURPOSE: Radiosurgical treatment of multiple intracranial targets using a single isocenter is more efficient than sequential isocenter treatment. The primary concern with single-isocenter, multitarget (SIMT) stereotactic...PURPOSE: Radiosurgical treatment of multiple intracranial targets using a single isocenter is more efficient than sequential isocenter treatment. The primary concern with single-isocenter, multitarget (SIMT) stereotactic radiosurgery (SRS) is that rotational error may cause underdosing of peripheral lesions and/or increased normal tissue toxicity, particularly for targets distant from the isocenter. Many centers mitigate this risk by adding a planning target volume (PTV) margin, which increases dose to normal brain tissue. This study examined whether distance from the isocenter affects local tumor control or toxicity in patients treated with SIMT SRS using a 0-mm PTV margin. METHODS AND MATERIALS: We retrospectively evaluated 429 patients with 3039 intracranial tumors treated with SIMT SRS or fractionated SRS using single-isocenter volumetric modulated arc therapy plans with a 0-mm clinical target volume/PTV expansion from gross tumor volume. All treatments used the Varian HD-120 multileaf collimators on a 6-degree-of-freedom couch. Local failure was defined as ≥25% increase in maximum tumor diameter (minimum 3 mm) or viable tumor cells at salvage surgery. Toxicity was defined as National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 central nervous system grade ≥3. RESULTS: Of the 3039 tumors evaluated, 1510 and 1034 tumors had clinical and radiographic follow-up at 6 months and 1 year, respectively. Median distance from the isocenter was 4.9 cm (range, 0.04-13.4 cm) and 70% of tumors in this study were ≥4 cm from the isocenter. One-year local control was 95.1% (95% CI, 94.0-96.1) and freedom from grade ≥3 toxicity was 98.4% (95% CI, 97.8-99.0). Larger tumor volume correlated with both worse local control (hazard ratio, 1.017; 95% CI, 1.000-1.034; P = .047) and higher toxicity (hazard ratio, 1.088; 95% CI, 1.056-1.121; P < .001). Increased distance from the isocenter was not associated with worse local failure or toxicity on multivariable analysis. CONCLUSIONS: In this retrospective analysis of SIMT volumetric modulated arc therapy radiosurgery using HD-120 multileaf collimators, 6-degree-of-freedom couch, intrafraction surface monitoring, and 0-mm clinical target volume/PTV margin, increased distance from the isocenter did not adversely impact short-term local tumor control or increase high-grade toxicity. These findings are currently being tested in a prospective randomized trial.
Dong H, Shih SF, Han F
… +7 more, Chin RK, Hayase JH, Bradfield JS, Bedayat A, Finn JP, Cao M, Zhong X
Int J Radiat Oncol Biol Phys
· 2026 Jun · PMID 42235692
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PURPOSE: Cardiac stereotactic body radiation therapy (SBRT) offers a noninvasive alternative to conventional radiofrequency catheter ablation for treating refractory ventricular tachycardia (VT) in patients who are poor...PURPOSE: Cardiac stereotactic body radiation therapy (SBRT) offers a noninvasive alternative to conventional radiofrequency catheter ablation for treating refractory ventricular tachycardia (VT) in patients who are poor candidates for ablation procedures. However, accurate target delineation remains challenging due to limited scar visualization on computed tomography and implanted cardioverter-defibrillator (ICD)-related magnetic resonance imaging (MRI) artifacts. We developed and evaluated a 3-dimensional (3D) wideband (WB) late gadolinium-enhanced (LGE) MRI protocol for artifact suppression, geometric accuracy, and scar delineation in SBRT planning. METHODS AND MATERIALS: The 3D WB LGE sequence employs a 6 kHz WB hyperbolic-secant inversion pulse to suppress ICD-induced hyperintense artifacts, followed by a 3D gradient-echo readout. Both electrocardiogram and respiratory navigator gating were employed to manage cardiac and respiratory motion, respectively. Protocol optimization was performed on phantoms and 4 healthy volunteers with ICDs positioned near the chest. Geometric distortion was measured using MagPhan and American College of Radiology phantoms. Clinical feasibility was tested in a 73-year-old patient undergoing cardiac SBRT. The 3D LGE MRI was registered with the planning computed tomography and compared with electroanatomic mapping using the American Heart Association 17-segment model. RESULTS: Phantom analysis showed minimal sequence-related distortion, well within clinical tolerance. ICD-induced distortion was negligible when the device was placed 10 cm from the target. The WB inversion pulse successfully suppressed ICD-related hyperintense artifacts in phantoms and healthy volunteers compared with conventional narrowband LGE MRI. In the VT patient, 3D WB LGE MRI enabled volumetric scar delineation, with good correlation between gadolinium enhancement and electroanatomic mapping-defined targets. Acquisition time for the 3D WB LGE MRI was optimized to approximately 5 minutes. CONCLUSIONS: 3D WB LGE MRI is feasible for cardiac SBRT simulation, achieving reliable suppression of ICD artifacts and minimal distortion while providing good noninvasive visualization of the scar. Its integration into clinical workflows may improve VT target delineation accuracy in patients with implanted devices.
Hu Z, Titt U, Li Y
… +10 more, Konradsson E, Aguilar EA, Neill DW, Connell L, Wang X, Meyer HJ, Gagea ML, McGovern SL, Schüler E, Mohan R
Int J Radiat Oncol Biol Phys
· 2026 Jun · PMID 42235691
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PURPOSE: Radiation‑induced musculoskeletal toxicities are one of the major limitations in pediatric patients whose skeletons are still developing. FLASH radiation therapy, delivered at ultrahigh dose rates (>40 Gy/s), ha...PURPOSE: Radiation‑induced musculoskeletal toxicities are one of the major limitations in pediatric patients whose skeletons are still developing. FLASH radiation therapy, delivered at ultrahigh dose rates (>40 Gy/s), has demonstrated normal-tissue sparing in preclinical models, but its effects on the developing skeleton and marrow remain incompletely characterized. This study evaluated the normal-tissue effects 10 weeks after proton FLASH irradiation in juvenile mice, modeling the pediatric context. METHODS AND MATERIALS: Juvenile C57BL/6 mice (3 to 4 weeks old) were randomized to receive 11 Gy protons with FLASH (≈200 Gy/s), conventional dose-rate irradiation (CONV, 0.2 Gy/s average), or sham treatment (SHAM) to the left hind leg using a synchrotron-based proton beamline. Mice were followed for 10 weeks posttreatment. Bone toxicity was assessed with micro-computed tomography, including bone mineral density, bone volume fraction, trabecular indices, and limb length. Bone marrow cellularity was quantified on hematoxylin and eosin-stained sections, and muscle fibrosis was assessed using Masson's trichrome staining. RESULTS: Proton FLASH irradiation preserved bone microarchitecture compared with conventional irradiation, with higher bone mineral density and bone volume fractions (P < .05). Trabecular number was maintained, while the structure model index indicated a mechanically favorable trabecular structure in the FLASH group. Proton FLASH also partially preserved longitudinal bone growth, with tibial length ratios of 0.94 (FLASH) versus 0.91 (CONV) versus 1.00 (SHAM). Bone marrow cellularity was preserved in FLASH mice (5.3% reduction vs SHAM) compared with CONV (11.3% reduction; P < .05). Muscle fibrosis was significantly lower in the FLASH group (fibrosis positivity 2.6% vs 3.0% for FLASH vs CONV; P < .05). No severe immobility or weight loss was observed across groups. CONCLUSIONS: Proton FLASH reduced musculoskeletal and marrow toxicities at 10 weeks postirradiation in juvenile mice. These findings extend prior proton FLASH adult mice studies by demonstrating tissue sparing in a juvenile model and support further investigation of FLASH as a strategy to reduce normal‑tissue injury during radiation therapy of pediatric patients.
Brennan MT, Passineau MJ, Saunders D
… +6 more, Sroussi H, Gaudilliere D, Liu J, Dubois N, Fernandez A, Zeldin RK
Int J Radiat Oncol Biol Phys
· 2026 May · PMID 42216935
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PURPOSE: Grade 2 and 3 late xerostomia is a chronic, debilitating complication of radiation therapy for head and neck cancers. We assessed the safety and efficacy of AAV2-hAQP1 gene therapy as a treatment for this condit...PURPOSE: Grade 2 and 3 late xerostomia is a chronic, debilitating complication of radiation therapy for head and neck cancers. We assessed the safety and efficacy of AAV2-hAQP1 gene therapy as a treatment for this condition. METHODS AND MATERIALS: Twenty-four participants who reported grade 2 and 3 late xerostomia at screening, ≥5 years after completing their final radiation therapy treatment (≥2 years if human papillomavirus-positive), were enrolled in this open-label, multicenter, dose-escalation study. AAV2-hAQP1 was delivered to the parotid gland(s) via cannulation of Stensen's duct. Twelve participants received AAV2-hAQP1 in 1 gland and 12 in both glands. Participants were followed for 12 months. Safety parameters included adverse events, physical examinations, laboratory tests, and electrocardiograms. Efficacy assessments included the Xerostomia-specific Questionnaire (XQ), MD Anderson Symptom Inventory-Head and Neck Module (MDASI-HN), Global Rate of Change Questionnaire (GRCQ), and measurement of unstimulated whole saliva flow rates (UWSFR). RESULTS: No treatment-related serious adverse events or dose-limiting toxicities were reported, and all participants completed the study. When the data from all cohorts were pooled, statistically significant improvements were seen on all patient-reported outcomes by day 30. These were maintained through month 12 with greater improvement in the bilateral cohort. At month 12, the mean percent change from baseline (%CFB) was -39.5% and -42.2% for the XQ Total Score and the MD Anderson Symptom Inventory-Head and Neck Module dry mouth question, respectively, and the mean GRCQ-Symptom Change Score was 3.8. Overall, 16 of 24 (67%) participants reported an improvement of ≥8 points in XQ Total Score, and 19 of 24 (79%) participants reported important improvements in xerostomia symptoms based on the GRCQ. The mean %CFB in UWSFR at month 12 was 112.5%. CONCLUSIONS: Treatment with AAV2-hAQP1 was safe and well-tolerated at all doses and resulted in meaningful improvements in xerostomia symptoms and UWSFR.
Mayadev J, Deng W, Kim H
… +13 more, Xiao Y, Chino JP, Kamrava MR, Leif J, Ghamande S, Rash D, Holman LL, Mathews C, Aghajanian C, Schilder R, Leath CA, O'Cearbhaill R, Zamarin D
Int J Radiat Oncol Biol Phys
· 2026 May · PMID 42184868
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OBJECTIVES: Advances in radiation (RT) treatment planning enhance the need for uniform quality oversight on clinical trials. NRG GY-017 was a randomized trial of the anti-program ligand death 1 (PD-L1) antibody, atezoliz...OBJECTIVES: Advances in radiation (RT) treatment planning enhance the need for uniform quality oversight on clinical trials. NRG GY-017 was a randomized trial of the anti-program ligand death 1 (PD-L1) antibody, atezolizumab, before and concurrent (arm A) or concurrent with chemoradiaton (arm B) for locally advanced cervical cancer. We describe the prospectively collected pretreatment RT quality and workflow. METHODS: Forty patients were consented and randomized. Thirty-seven patients submitted pretreatment RT plans for central review, and 36 patients ultimately received protocol therapy. Intensity modulated radiation therapy (IMRT) contouring guidelines and dose specifics were outlined in the protocol, with volume and dose deviations specified as per protocol, minor and major variation. Each site had to pass a standardized IMRT credentialing process. Sites were required to submit an IMRT plan for physician expert contour target and organ-at-risk review in a rapid pretreatment manner. An expert physician then scored the contours and plan as per protocol or as a deviation. For major deviations, the sites were required to revise and resubmit the plans, which were then re-reviewed prior to protocol start. RESULTS: The median follow-up time was 20 months. Thirty-seven participants had a central expert review of the pretreatment external beam radiation therapy plan. Thirteen plans (35%) were scored as a major deviation requiring revision: 11 secondary to contours (5 bowel and 6 nodal volumes) and 2 secondary to incorrect expansion on the volume or the dose distribution. The major deviation plans were resubmitted; however, 2 of them required revisions for a total of 3 plans. Because of the quality review, all patients had per-protocol scores prior to the treatment administration. CONCLUSIONS: Our data indicate that 35% of the baseline submitted advanced technology IMRT plans required revision and resubmission in order to meet protocol standards. RT plan quality workflow continues to evolve with advanced techniques and has implications in clinical trial review. Pretreatment plan review is an important quality measure for cervical cancer clinical trials.
Petit C, Phan J, Ng SP
… +17 more, Filion E, Lee N, Poon I, Palma DA, Yom SS, Lee J, Heron DE, Siddiqui F, Liem X, Yamazaki H, Foote RL, Lo SS, Caudell J, Biau J, Karam I, Nguyen-Tan PF, Bahig H
Int J Radiat Oncol Biol Phys
· 2026 May · PMID 42176868
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BACKGROUND: The role of SABR in head and neck cancer remains uncertain. Historically, it has been used mainly for reirradiation, and its application in other clinical scenarios has expanded with recent advances. OBJECTIV...BACKGROUND: The role of SABR in head and neck cancer remains uncertain. Historically, it has been used mainly for reirradiation, and its application in other clinical scenarios has expanded with recent advances. OBJECTIVE: To develop an international expert consensus on indications, technical parameters, and clinical application of head and neck SABR using a modified Delphi process. METHODS: A three-round modified Delphi process was conducted between July 2021 and January 2023. Radiation oncologists with experience in head and neck SABR were invited to participate. Round 1 consisted of open-ended questions. Rounds 2 and 3 involved rating agreement with 103 statements addressing indications, contraindications, planning, dose and fractionation, toxicity mitigation, systemic therapy integration, and follow-up. Consensus was defined as ≥75% agreement, and major agreement as 65% to 74%. RESULTS: Seventeen of 26 invited experts (65.4%) completed all rounds, with representation from North America, Europe, and Asia-Oceania. Of the 103 statements, 56 (54.3%) reached consensus, and 12 (11.7%) achieved major agreement. Consensus supported SABR for reirradiation of small isolated recurrences, unresectable tumors, or second primaries in previously irradiated fields, and oligometastatic lesions in untreated patients. Use in local palliation and in patients unfit for standard fractionation within a clinical trial also met consensus. No consensus was reached for postoperative SABR, including its use for positive margins or extranodal extension, nor for SABR boost in first-course treatment. Technically, consensus favored volumetric modulated arc therapy, tight planning target volume margins of 2 to 3 mm, multimodality imaging (thin-slice computed tomography, magnetic resonance imaging, and positron emission tomography/computed tomography), and daily volumetric imaging with physician verification. Clinical target volume expansion was discouraged, and elective nodal irradiation was not recommended. Every-other-day fractionation and dose reduction near critical structures were endorsed. Consensus emphasized counseling on key toxicities and supported imaging at 2 to 3 months post-SABR. No consensus was reached on systemic therapy integration. CONCLUSION: This multi-institutional Delphi study provides expert-derived recommendations reflecting the current state of head and neck SABR practice and identifies priorities for future research.
Thonglert K, Greer MD, Schaub SK
… +7 more, Bowen SR, Nyflot MJ, Grassberger C, Menghini AM, Kim EY, Wong T, Apisarnthanarax S
Int J Radiat Oncol Biol Phys
· 2026 May · PMID 42176867
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PURPOSE: Optimal management of large, unresectable hepatocellular carcinoma (HCC) remains uncertain. Proton beam therapy (PBT) offers dosimetric advantages for sparing the normal liver. Clinical outcomes for these patien...PURPOSE: Optimal management of large, unresectable hepatocellular carcinoma (HCC) remains uncertain. Proton beam therapy (PBT) offers dosimetric advantages for sparing the normal liver. Clinical outcomes for these patients in Western populations are limited. This study evaluated clinical outcomes, toxicity, and patterns of failure among Western patients with large localized HCC treated with PBT. METHODS AND MATERIALS: A retrospective single-institution cohort of patients with HCC tumors ≥5 cm, ineligible for surgery or other liver-directed therapies, and treated with PBT was analyzed. Patients with uncontrolled extrahepatic metastases, concurrent systemic therapy, or mixed histology were excluded. All patients received 45.0 to 67.5 Gy(RBE) in 15 fractions. Competing risk and Kaplan-Meier methods were used to assess local failure (LF), overall survival (OS), progression-free survival, and radiation-induced liver disease (RILD). Univariate Cox regression evaluated predictors of OS, LF, and nonclassic RILD. RESULTS: Fifty-one patients met the criteria and had the following high-risk features: Barcelona Clinic Liver Cancer stage C (45%), Child-Pugh (CP)-B/C cirrhosis (26%), vascular invasion (39%), and a median tumor size of 9.2 cm. Median follow-up for survivors was 51 months. The 1-, 2-, and 3-year cumulative incidences of LF were 4%, 13%, and 13%, respectively. Most failures were out-of-field intrahepatic (50%) or distant (21%); only 4% developed isolated LF. One-, 2-, and 3-year OS rates were 65%, 46%, and 30%, respectively. Tumor size independently predicted OS (HR, 1.18; P < .01). Nonclassic RILD occurred in 15% and was 6% in CP-A and 43% in CP-B+ patients. CONCLUSIONS: Dose-escalated PBT achieves excellent local control with acceptable toxicity for large HCC in Western patients, including tumors >10 cm. Patients with preserved liver function derive the greatest benefit, whereas those with CP-B cirrhosis have higher hepatotoxicity risks. Out-of-field intrahepatic and distant progression remain dominant failure patterns, highlighting opportunities to integrate systemic therapy with definitive PBT.
Paillas S, Then CK, Suárez-Bonnet A
… +7 more, Priestnall SL, Kumaran G, Ruan JL, Tullis IDC, Olcina MM, Bottomley MJ, Petersson K
Int J Radiat Oncol Biol Phys
· 2026 May · PMID 42176866
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PURPOSE: FLASH radiation therapy shows promise in reducing normal tissue toxicity compared with conventional radiation therapy. Although several studies report skin-sparing effects of FLASH, few have quantitatively asses...PURPOSE: FLASH radiation therapy shows promise in reducing normal tissue toxicity compared with conventional radiation therapy. Although several studies report skin-sparing effects of FLASH, few have quantitatively assessed this effect or explored underlying immunological mechanisms. METHODS AND MATERIALS: We quantified the skin-sparing effect of FLASH after single and fractionated hemithorax irradiation in mice. Multiplex gene expression analysis and immune profiling were performed to assess the immune status of irradiated skin. We also investigated the impact of CD8 T-cell depletion for the different irradiation conditions. RESULTS: FLASH irradiation significantly delayed the onset and reduced the severity of skin toxicity compared with conventional irradiation for both single and fractionated irradiation (P < .001), with a dose-modifying factor of ≈1.5 after single dose irradiation and a similar level of dose-modifying factor (∼1.5) for fractionated irradiation. FLASH-irradiated mice showed dampened immune activation and greater preservation of immune cell populations. CD8 T-cell depletion exacerbated skin toxicity and inflammatory response after conventional but not FLASH irradiation. CONCLUSIONS: Conventional radiation-induced skin toxicity is dose dependent and strongly linked to subsequent immune dysfunction, with stronger toxicity under immunocompromised conditions. FLASH irradiation provides significant reduction in skin toxicity, an effect maintained with hypofractionated regimens and in immunocompromised conditions. These findings underscore the clinical potential of FLASH radiation therapy, where normal tissue toxicity limits treatment and reveal an immune-mediated contribution to its protective effect.
Int J Radiat Oncol Biol Phys
· 2026 May · PMID 42176865
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PURPOSE: Recently, results from National Surgical Adjuvant Breast and Bowel Project; Radiation Therapy Oncology Group; Gynecologic Oncologic Group (NRG/RTOG) 0924, the largest randomized trial to evaluate the benefit of...PURPOSE: Recently, results from National Surgical Adjuvant Breast and Bowel Project; Radiation Therapy Oncology Group; Gynecologic Oncologic Group (NRG/RTOG) 0924, the largest randomized trial to evaluate the benefit of whole-pelvic radiation therapy (WPRT) in localized prostate cancer, were presented. We conducted an aggregate meta-analysis of all phase III randomized trials to determine the impact of WPRT on oncologic outcomes. METHODS: PubMed via MEDLINE, clinicaltrials.gov, and conference proceedings were systematically searched for randomized trials of ±WPRT in localized prostate cancer conducted between 1980 and 2025. Random-effects models were used to generate pooled hazard ratios (HRs) with 95% CIs. Heterogeneity was assessed with I statistics, and leave-one-out sensitivity analyses were performed. Meta-regression was performed to assess the influence of the proportion of patients with Gleason score 7 to 10, use of androgen deprivation therapy, radiation therapy dose, and field size. Endpoints assessed included overall survival, a biochemical-based endpoint, referred to as biochemical recurrence, and distant metastasis. RESULTS: Four randomized trials were identified (n = 4465 patients), including 3 multicenter cooperative group trials Urogenital Tumor Study Group-French Association of Urology (GETUG-AFU-01, RTOG 9413, and RTOG 0924) and 1 single-institution trial Prostate-Only versus Whole-Pelvic Radiation Therapy (POP-RT). WPRT did not improve overall survival (HR, 1.05; 95% CI, 0.95-1.16; I = 0%), biochemical recurrence (HR, 0.82; 95% CI, 0.63-1.07; I = 76%), or distant metastasis (HR, 0.88; 95% CI, 0.58-1.34; I = 68%). The high rates of heterogeneity observed were due primarily to the POP-RT trial. In sensitivity analyses, excluding POP-RT heterogeneity was eliminated (HR for biochemical recurrence was 0.91 [95% CI, 0.81-1.02; I = 0%]; HR for distant metastasis was 1.06 [95% CI, 0.87-1.29; I = 0%]). Meta-regression found no significant modifying effect of any covariables assessed. CONCLUSIONS: This aggregate meta-analysis did not demonstrate any meaningful benefit of WPRT over prostate-only radiation therapy in unselected localized prostate cancer. Individual patient data meta-analysis is warranted to understand whether any subgroup consistently derives benefit from WPRT.
Wu L, Masaki N, Mukohara T
… +21 more, Yang J, Sun Z, Ren C, Chen D, Jiang K, Tang Q, Ding K, Yin X, Yu H, Zhou Y, Wang S, Yin J, Yan Y, He Y, Li Q, Wei W, Lu Z, Sun X, Ma C, Ye X, Yan S
Int J Radiat Oncol Biol Phys
· 2026 May · PMID 42176864
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PURPOSE: Radiation pneumonitis (RP) is a dose-limiting toxicity in lung cancer radiation therapy, often poorly predicted by static clinical and dosimetric models. We aimed to identify a robust, blood-based proteomic sign...PURPOSE: Radiation pneumonitis (RP) is a dose-limiting toxicity in lung cancer radiation therapy, often poorly predicted by static clinical and dosimetric models. We aimed to identify a robust, blood-based proteomic signature grounded in the longitudinal biological response to radiation to enable accurate, early risk stratification. METHODS AND MATERIALS: We conducted a prospective study using high-throughput plasma proteomics on 267 longitudinal samples from a discovery cohort of 57 patients with lung cancer (non-small cell lung cancer and small cell lung cancer). To ensure statistical rigor and eliminate data leakage, feature selection was performed strictly within a 70% training partition. Linear mixed-effects models and Weighted Gene Co-expression Network Analysis were used to identify protein trajectories associated with symptomatic RP (Common Terminology Criteria for Adverse Events v5.0 grade ≥ 2). An Elastic Net machine learning model was developed and evaluated on an independent test set. The 10-protein signature was subsequently validated via enzyme-linked immunosorbent assay in a large, independent external cohort (n = 320). RESULTS: Longitudinal analysis identified a dysregulated immuno-thrombotic axis as a central driver of RP, characterized by significant enrichment in "Platelet Activation" and "Serpin" pathways. In patients experiencing grade ≥ 2 RP, we observed a "systemic exhaustion" profile marked by the progressive decline of key anticoagulant and anti-inflammatory proteins. The 10-protein model achieved an unbiased area under the curve of 0.744 (95% CI: 0.622-0.861), outperforming a baseline clinical model (area under the curve = 0.679). External validation in 320 patients confirmed the robustness of a 4-protein clinical core (PROZ, SERPINA7, SERPINA6, and HAGH), with Pvalues ranging from 10 to 10. This signature remained a significant independent predictor (P < .05) after adjusting for mean lung dose, V20, and immunotherapy status, and was distinct from markers of overall survival. CONCLUSIONS: A systemic immuno-thrombotic signature accurately predicts RP across different histologies and treatment regimens. This validated 4-protein core provides a clinically transportable tool for early risk stratification and personalized toxicity mitigation.