The clinical benefit of extending tumor treating fields (TTFields) beyond concurrent chemoradiotherapy (CRT) for newly diagnosed glioblastoma (ndGBM) is unclear. This multi-institutional retrospective study compared patients who continued TTFields into adjuvant temozolomide (CRT-TT, n = 68) versus those who discontinued after CRT (CRT-T, n = 32). With a median follow-up of 36.9 months, median progression-free survival (mPFS) did not significantly differ between the groups (12.8 vs. 12.5 months; hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.57-1.59; p = 0.853) nor did median overall survival (mOS) (20.6 vs. 16.6 months; HR 0.73, 95% CI 0.43-1.27; p = 0.267). Additionally, continuing TTFields into the adjuvant phase did not increase scalp toxicity. Although a numerically longer OS was seen in the CRT-TT group, the lack of statistical significance may reflect limited power and non-randomized allocation. These findings underscore the need for further investigation.

Purpose:The combination of radiotherapy with immunotherapy holds synergistic potential, yet its role in the neoadjuvant treatment of breast cancer remains underexplored. This single-center, retrospective pilot study aimed to explore the preliminary efficacy and safety of integrating stereotactic body radiotherapy (SBRT) with chemoimmunotherapy as a novel neoadjuvant regimen for a small cohort of patients with high-risk, locally advanced breast cancer. Patients and Methods:Between June 2023 and August 2025, 20 patients received neoadjuvant SBRT (18Gy/3 fractions for node-positive; 24Gy/3 fractions for node-negative disease) concurrently with chemoimmunotherapy (various anti-PD-1/bispecific antibodies plus chemotherapy), followed by surgery. Key endpoints were pathological complete response (pCR, ypT0/Tis ypN0), near-pCR (Residual Cancer Burden [RCB] class 0 or I), objective response rate (ORR), and safety. Results:The cohort included triple-negative breast cancer (TNBC, 35%) and hormone receptor-positive/HER2-negative breast cancer of the Luminal B subtype (Luminal B/HER2-, 50%). Most had cT2 (75%) and node-positive (75%) disease. The median number of chemoimmunotherapy cycles were 8, with 80% receiving an AC-T backbone. The overall pCR rate was 45% (9/20). Efficacy varied by subtype: the pCR rate was 85.7% (6/7) in TNBC and 20% (2/10) in Luminal B/HER2- disease. Notably, 100% of TNBC and 40% of Luminal B/HER2- patients achieved near-pCR (RCB 0/I). ORR was 90%. Grade 3-4 adverse events occurred in 25% of patients, with no treatment-related mortality. Conclusion:In this single-center, retrospective pilot study, early integration of SBRT with chemoimmunotherapy demonstrated promising antitumor activity, particularly high pCR rates in TNBC and induction of deep pathological responses (RCB 0/I) in Luminal B/HER2- disease, with a manageable safety profile. Observed in a heterogeneous cohort, these preliminary findings highlight potential efficacy but require cautious interpretation and warrant validation in larger, prospective trials.

Background Predicting the occurrence and/or severity of oral mucositis (OM) before commencing radiotherapy (RT) remains very difficult. The aim of this prospective trial was to investigate whether the ex-vivo radiation sensitivity of oral keratinocytes from head and neck (H&N) cancer patients correlates with severe OM. Methods Oral microbiopsies of healthy gingival mucosa were collected from 63H&N cancer patients undergoing (chemo)RT, of which 58 samples were useable. Keratinocytes from these microbiopsies underwent ex-vivo proliferation, irradiation, and subsequently the cell spreading assay. Tubes with the cell suspension were placed within the irradiation chamber of a 137Cs Gammacell 40 Exactor (Best Theratronics, Canada) and exposed to 0, 2, 4, 6, or 8 Gy at a dose rate of 0.63 Gy min−1. Cell suspension was then immediately pipetted into custom-made polydimethylsiloxane (PDMS) rings.The effect of demographic and clinical parameters on the cell spreading assay were also analyzed. Systematic clinical recording of OM was conducted twice a week by a specially trained examiner. Results Most patients had node-positive disease and cancer of the oropharynx or oral cavity. The vast majority of patients received adjuvant RT and concurrent chemotherapy. Overall, 34 (58.6 %) participants developed grade 3 OM after a median dose of 32 Gy. No patient experienced a grade ≥ 4 event. There was a correlation between the cell spreading assay area and grade 3 OM (p < 0.05), equivalent to approximately 0.5 Gy dose. Demographic and clinical parameters had no significant impact on the cell spreading assay (p > 0.05 for all). Conclusions It is necessary to establish reliable predictors of severe OM before treatment in H&N cancer to allow early management of treatment-related sequelae. This prospective trial illustrates that the intrinsic ex-vivo radiosensitivity of oral keratinocytes could be correlated with RT-induced OM in patients with H&N cancer. This novel predictor requires validation in larger prospective cohorts.

BACKGROUND/AIM:The 21-gene assay recurrence score (RS) can guide the use of chemotherapy for the management of patients with pN0- 1 [1-3 positive lymph nodes (LNs)] breast cancer. However, practice patterns based on this assay, as well as associated outcomes, have not been evaluated for patients with pN2 (4-9 positive LNs) disease. PATIENTS AND METHODS:The National Cancer Database (NCDB) was queried for patients with newly-diagnosed, non-metastatic, hormone receptor-positive, Her2-negative, pN2 breast cancer who underwent adjuvant endocrine therapy and had a known RS. Kaplan-Meier analysis was used to evaluate overall survival (OS); Cox proportional hazards modeling determined variables associated with OS. RESULTS:Of 1,658 patients, 1,109 (67%) received chemotherapy and 549 (33%) did not. Chemotherapy was administered to 54% of patients with a low-risk recurrence score (RS), 67% with intermediate-risk RS, and 75% with high-risk RS. Chemotherapy was associated with improved 5-year OS in low-risk RS (95.5% vs. 87.4%), intermediate-risk RS (91.9% vs. 83.5%), and high-risk RS (81.3% vs. 50.2%) (p≤0.001 for all). On Cox multivariable analysis, chemotherapy and the RS risk group significantly associated with OS (p<0.05 for both). Qualitatively, patients over 70 years of age appeared to benefit comparatively less from chemotherapy. CONCLUSION:Despite the underutilization of chemotherapy for hormone receptor-positive, Her2-negative, pN2 patients, it was associated with improved OS for all 21-gene panel risk groups. These results support the existing standard of chemotherapy for this population, although omission could be considered in patients over 70 years of age.

PURPOSE:A single-phase 3 trial has demonstrated that prostate radiation therapy with a focal, intraprostatic "microboost" can improve disease control without an overall increase in toxicity. It is unclear how these results generalize to other treatment schedules and protocols. METHODS AND MATERIALS:A systematic search of PubMed and the Cochrane review was performed for studies published on or before September 1, 2023. A random-effects meta-analysis was used to pool the cumulative incidence of grade ≥2 (≥G2) acute and late genitourinary (GU) and gastrointestinal (GI) toxicity. Heterogeneity was assessed, and the association of trial-level covariates with toxicity was examined via the subgroup analyses and meta-regression. Odds ratios (ORs) for dose metrics were reported per Gy equivalent dose in 2Gy per fraction (EQD2). RESULTS:Thirty-eight patient cohorts were included. The pooled estimate of the cumulative incidence of ≥G2 acute and late GU toxicity was 25.3% (95% CI, 19.1%-32.8%) and 21.1% (95% CI, 16.7%-26.3%), respectively. Late ≥G2 GI toxicity was less frequent, estimated at 5.6% (95% CI, 3.5%-8.7%) and 6.9% (95% CI, 4.6%-10.1%), respectively. Subgroup factors associated with at least one ≥G2 toxicity category were treatment technique, imaging used for boost volume definition, intrafraction motion management, trial phase, and toxicity grading. Rectal DMax was associated with acute ≥G2 GI toxicity (OR, 1.05; 95% CI, 1.02-1.08; P < .001). Additionally, urethral DMax was associated with late ≥G2 GU toxicity (OR, 1.02; 95% CI, 1.01-1.03; P < .001), and a stronger relationship was observed with the average plan urethral DMax (OR, 1.05; 95% CI, 1.03-1.07; P < .001). No association of toxicity with any bladder dose metric examined was observed. CONCLUSIONS:The utilization of a microboost seems tolerable across treatment protocols; however, subgroup factors, including the use of intrafraction motion management and the type of imaging modality used, may influence the probability of toxicity. Attention to rectal DMax constraints and urethral DMax dose constraints may help to mitigate GI and GU toxicity, respectively. No association between toxicity and bladder dose constraints was observed.

Mitochondria regulate T cell functions and response to immunotherapy. We show that pyruvate kinase M2 (PKM2) activation enhances mitochondria-dependent effector functions in CD8 and chimeric antigen receptor (CAR)-T cells. Multi-omics and 13C-glucose tracer studies showed that PKM2 agonism alters one-carbon metabolism, decreasing methionine levels, resulting in hypomethylated nuclear and mitochondrial DNA and enhancing mitochondrial biogenesis and functions. PKM2 activation increased the recall responses and anti-tumor functions of CD8 T cells, enhancing adoptive cell therapy. In preclinical models, the PKM2 agonist induced CD8 T cell-dependent anti-tumor responses that synergized with anti-programmed death 1 (PD1) therapy. Immunologically, PKM2 agonists boosted the activation of effector T cells while reducing FoxP3+ T regulatory (Treg) cells in the tumors. The anti-PD1 combination enhanced the frequency of tumor-specific activated CD8 T cells. Together, PKM2 agonism increased mitochondrial functions supporting cell cytotoxicity. Hence, pharmacological targeting of PKM2 can be a clinically viable strategy for enhancement of adoptive cell therapy, in situ anti-tumor immune responses, and immune checkpoint blockade therapy. VIDEO ABSTRACT.

BACKGROUND:The recent phase II randomized stereotactic ablative radiotherapy with and without immunotherapy (I-SABR) trial has shown improved event-free survival (EFS) when adding immunotherapy to stereotactic ablative radiotherapy (SABR) for early-stage inoperable non-small cell lung cancer (NSCLC). However, optimizing patient selection thereof is critical, because not every patient benefits from immunotherapy. Leveraging the powerful use of artificial intelligence, this secondary analysis of the I-SABR trial developed a modeling system (named "I-SABR-SELECT") based on clinical and radiomic factors to address which patients should receive additional immunotherapy. METHODS:The discovery/validation cohorts were from the I-SABR trial, with external validation from the single-arm STARS trial. Individual treatment effect scores, estimating the benefit of adding immunotherapy, were derived from radiomic and clinical predictors using counterfactual reasoning. Dimensionality reduction was applied to mitigate overfitting and enhance model robustness. We also evaluated the average treatment effect between subgroups of patients who were treated following versus against the model's recommendation. RESULTS:The model recommended that 49% (69/141) patients enrolled in the I-SABR trial switch treatments (65% (49/75) in the SABR arm and 30% (20/66) in the I-SABR arm). Patients treated by the model's recommendation had higher EFS, with HRs of 0.06 (in the I-SABR arm, p<0.001) and 0.26 (in the SABR alone arm, p=0.0042) from the I-SABR trial population, and 0.38 (p=0.031) for the STARS trial. Following model stratification, among patients recommended for SABR+immunotherapy, the restricted mean survival time for EFS is prolonged by 1.43 years compared to those who received SABR alone. The absolute risk reduction of the added immunotherapy effect was over twofold greater than that observed in the I-SABR trial without selection. CONCLUSIONS:Combining clinical and radiomic parameters, I-SABR-SELECT uses causal reasoning to individualize treatment selection for patients with early-stage inoperable NSCLC. If validated, it could serve as a foundation for a treatment-focused digital twin by integrating real-time adaptive decision-making. Code: https://github.com/WuLabMDA/ISABR-SELECT.

Small cell lung cancer (SCLC) is difficult to treat due to its aggressiveness, early metastasis, and rapid development of resistance to chemotherapeutic agents. Here, we show that treatment with a dopamine D2 receptor (D2R) agonist reduces tumour angiogenesis in multiple in vivo xenograft models of human SCLC, thereby reducing SCLC progression. An FDA-approved D2R agonist, cabergoline, also sensitized chemotherapy-resistant SCLC tumours to cisplatin and etoposide in patient-derived xenograft models of acquired chemoresistance in mice. Ex vivo, D2R agonist treatment decreased tumour angiogenesis through increased apoptosis of tumour-associated endothelial cells, creating a less favourable tumour microenvironment that limited cancer cell proliferation. In paired SCLC patient-derived specimens, D2R was expressed by tumour-associated endothelial cells obtained before treatment, but D2R was downregulated in SCLC tumours that had acquired chemoresistance. D2R agonist treatment of chemotherapy-resistant specimens restored expression of D2R. Activation of dopamine signalling is thus a new strategy for inhibiting angiogenesis in SCLC and potentially for combatting chemotherapy-refractory SCLC progression.

PURPOSE:Immunoradiation therapy, the combination of radiation therapy (RT) and immunotherapy, represents a promising advancement in cancer treatment by enhancing local and systemic tumor control and improving patient response rates. Although RT has long been a cornerstone of oncologic care, its efficacy is often limited by various tumor resistance mechanisms. Immunotherapy, which leverages the immune system to combat cancer, offers a complementary means to enhance RT's effectiveness. This review aims to provide a real-world guide for optimizing immunoradiation therapy in clinical practice and to bridge the gap between research and clinical application. METHODS AND MATERIALS:This review synthesizes current literature and clinical experience related to the integration of immunotherapy and RT, focusing on four critical areas: pretreatment factors, immunotherapy sequencing, RT planning, and posttreatment follow-up. Key considerations include prior patient treatments, the timing and type of immunotherapy, radiation dosing and fractionation strategies, tumor size, organs at risk, and effective post-RT monitoring, which collectively will help tailor a precise approach. In addition, the review highlights emerging approaches that incorporate artificial intelligence into RT planning and the development of personalized immunoradiation therapy. RESULTS:Evidence from recent studies demonstrates that the combination of RT and immunotherapy can enhance both local tumor control and systemic immune activation. To dissect further, the results of our review emphasize the importance of variables impacting treatment outcomes such as: prior chemotherapy, use of steroids, absolute lymphocyte counts, radiation dose and sequencing of immunotherapy in regard to RT, avoiding organs at risk, devising novel lymphocyte sparing techniques, and pulsed RT approach in cases of progression. CONCLUSIONS:By addressing the key factors influencing treatment design and implementation, immunoradiation therapy can be effectively tailored to improve therapeutic outcomes. Furthermore, the integration of artificial intelligence and multidisciplinary coordination may help in automated planning, treatment precision, and advancing personalized care in clinical oncology.

Radiotherapy and immunotherapy - both important facets of modern cancer treatment - provide therapeutic benefits, but also raise concerns from potential concomitant adverse effects. One such adverse event, treatment-associated pneumonitis (TAP), can cause profound changes in quality of life of patients with thoracic malignancies. The aim of this review is to elucidate the pathogenesis, incidence, risk factors, differential diagnosis, and management of pneumonitis induced by the combination of radiotherapy and immunotherapy for lung cancer.

Immune checkpoint inhibitors (ICIs), either as monotherapy (ICI-Mono) or combined with chemotherapy (ICI-Chemo), improves survival in advanced non-small cell lung cancer (NSCLC). However, prospective guidance for choosing between these options remains limited, and single-feature biomarkers like PD-L1 prove inadequate. We develop a machine learning model using clinicogenomic data from four cohorts (MD Anderson n = 750; Mayo Clinic n = 80; Dana-Farber n = 1077; Stand Up To Cancer n = 393) to predict individual benefit from adding chemotherapy. Benefit scores are calculated using five distinct functions derived from 28 genomic and 6 clinical features. Our integrated model, A-STEP (Attention-based Scoring for Treatment Effect Prediction), estimates heterogeneous treatment effects and achieves the largest reduction in 3-month progression risk, improving weighted risk reduction by 13-23% over stand-alone models. A-STEP recommends treatment changes for over 50% of patients, most often favoring ICI-Chemo. In simulation on external cohort, patients treated in accordance with A-STEP recommendations show improved 2-year progression-free survival (HR = 0.60 for ICI-Mono treatment arm; HR = 0.58 for ICI-Chemo treatment arm). Predictive features include FBXW7, APC, and PD-L1. In this study, we demonstrate how machine learning can fill critical gaps in immunotherapy selection for NSCLC, by modeling treatment heterogeneity with real-world clinicogenomic data, driving precision medicine beyond conventional biomarker boundaries.

Oral mucositis (OM) is a frequently reported radiotherapy (RT)-induced acute toxicity in head and neck (H N) cancer patients. Severe OM may be a dose-limiting condition, which can affect oncological outcomes. Therefore, we conducted a pooled analysis of two prospective studies with long-term follow-up to evaluate the impact of grade ≥3 OM on outcomes. This pooled analysis included 253 H N cancer patients who received primary definitive or adjuvant chemoradiotherapy at the University of Freiburg Medical Center. Kaplan–Meier analyses with log-rank tests stratified for the presence of grade 3 OM were performed for overall survival (OS), local recurrence-free survival (LRFS), and distant-metastasis free survival (DMFS). Univariate Cox proportional hazards regression was performed to identify prognostic factors for OS, LRFS, and DMFS. The majority of participants had locally advanced disease: UICC stage IVA in 157 (62.1

Purpose: To report demographic and clinical characteristics of patients who were more likely to receive proton beam therapy (PBT) than photon therapy from facilities with access to proton centers. Materials and Methods: We utilized the national cancer database to identify the facilities with access to PBT between 2004 and 2015 and compared the relative usage of photons and PBT for demographic and clinical scenarios in breast, prostate, and nonsmall cell cancer. Results: In total, 231 facilities with access to proton centers accounted for 168 323 breast, 39 975 lung, and 77 297 prostate cancer patients treated definitively. Proton beam therapy was used in 0.5%, 1.5%, and 8.9% of breast, lung, and prostate cases. Proton beam therapy was correlated with a farther distance traveled and longer start time from diagnosis for each site (P < .05). For breast, demographic correlates of PBT were treatment in the west coast (odds ratio [OR] = 4.81), age <60 (OR = 1.25), white race (OR = 1.94), and metropolitan area (OR = 1.58). Left-sided cancers (OR = 1.28), N2 (OR = 1.71), non-ER+/PR+/Her2Neu- cancers (OR = 1.24), accelerated partial breast irradiation (OR = 1.98), and hypofractionation (OR = 2.35) were predictors of PBT. For nonsmall cell cancer, demographic correlates of PBT were treatment in the south (OR = 2.6), metropolitan area (OR = 1.72), and Medicare insurance (OR = 1.64). Higher comorbid score (OR = 1.36), later year treated (OR = 3.16), and hypofractionation (not SBRT) (OR = 3.7) were predictors of PBT. For prostate, correlates of PBT were treatment in the west coast (OR = 2.48), age <70 (OR = 1.19), white race (OR = 1.41), metropolitan area (OR = 1.25), higher income/education (OR = 1.25), and treatment at an academic center (OR = 33.94). Lower comorbidity score (OR = 1.42), later year treated (OR = 1.37), low-risk disease (OR = 1.45), definitive compared to postoperative (OR = 6.10), and conventional fractionation (OR = 1.64) were predictors of PBT. Conclusion: Even for facilities with established referrals to proton centers, PBT utilization was low; socioeconomic status was potentially a factor. Proton beam therapy was more often used with left-sided breast and low-risk prostate cancers, without a clear clinical pattern in lung cancer.

Importance:Several locoregional therapies (LRTs) for nonmetastatic hepatocellular carcinoma (HCC) are available; however, a global comparison of the relative efficacy of each is needed. Objective:To conduct a systematic review and direct, pairwise meta-analytic comparison of all identified randomized clinical trials evaluating the treatment of nonmetastatic HCC. Data Sources:A comprehensive search of PubMed and the proceedings of the American Society of Clinical Oncology and American Society for Radiation Oncology annual meetings from January 1, 2010, to November 1, 2023, was performed. Study Selection:Randomized clinical trials using a form of LRT (surgery with or without adjuvant therapy, radiofrequency ablation [RFA], microwave ablation [MWA], radiotherapy [RT], hepatic arterial infusion chemotherapy [HAIC], transarterial bland embolization [TAE], transarterial chemoembolization [TACE], or transarterial radioembolization [TARE]). Data Extraction and Synthesis:Study eligibility and data extraction were each reviewed by 2 authors independently. Random-effects meta-analyses were used to compare treatment categories. Main Outcomes and Measures:Progression-free survival (PFS) was the primary outcome; overall survival (OS) was the secondary outcome. Results:Forty randomized clinical trials reporting on comparative outcomes of 11 576 total patients with localized HCC treated with LRT were included. The median follow-up was 30.0 (IQR, 18.5-40.8) months. Direct pooled comparisons between treatment classes suggested improved outcomes for surgery combined with adjuvant therapy over surgery alone (PFS: hazard ratio [HR], 0.62 [95% CI, 0.51-0.75]; P < .001; OS: HR, 0.61 [95% CI, 0.48-0.78]; P < .001), surgery over RFA (PFS: HR, 0.74 [95% CI, 0.63-0.87]; P < .001; OS: HR, 0.71 [95% CI, 0.54-0.95]; P = .02), RT over TACE (PFS: HR, 0.35 [95% CI, 0.21-0.60]; P < .001; OS: HR, 0.35 [95% CI, 0.13-0.97]; P = .04), and HAIC over TACE (PFS: HR, 0.57 [95% CI, 0.45-0.72]; P < .001; OS: HR, 0.58 [95% CI, 0.45-0.75]; P < .001). No substantial heterogeneity was noted for any pairwise comparison with the exception of RT-based regimens compared with tyrosine kinase inhibitor therapy. Conclusions and Relevance:The findings of this systematic review and direct, pairwise meta-analysis suggest that all LRTs are not equivalent for the treatment of localized HCC. The efficacy of LRTs appears hierarchical, with surgery-based management outcomes associated with the best treatment outcomes and embolization-based treatment options associated with the worst treatment outcomes.

Despite the promise of combining immunotherapy and radiotherapy (RT) for metastatic cancers, existing randomized data have not been consistent on whether RT to a single irradiated site improves clinical outcomes. Mechanistically, this could result from a low quantity/diversity of tumor antigens released for immune detection, immunosuppressive molecules released by tumor masses, and the lack of immune infiltration into tumor bulk. Herein, multi-site RT is discussed as a potential solution, given that it can directly improve upon each of the mechanistic issues. Just as it is illogical to use systemic therapy alone in place of a dedicated local therapeutic option (e.g., RT) for most stage II-III malignancies, so too is illogical to irradiate one site only in case of metastatic neoplasms instead of implementing systemic therapy and/or multi-site RT. Although it may theoretically be possible to address all systemic disease with systemic therapy, that notion assumes that all areas of systemic disease will be responsive to systemic therapy in the first place. However, in reality, certain sites may develop innate or acquired resistance to systemic therapy, hence opening the door to multi-site localized treatment strategies. Further investigation is required to address whether multi-site RT would be effective in the setting of suboptimal immune function and/or resistance/refractoriness to multiple prior systemic therapies. Methods to improve the effectiveness of multi-site RT are also discussed, such as ablatively-/definitively-dosed RT, along with staggered timing of RT administration (pulsed RT).

BACKGROUND:All known randomized trials of stereotactic radiotherapy (SRT) versus whole brain radiotherapy (WBRT) for brain metastases (BMs) comprise mixed histologies. The phase III HYBRID trial (NCT02882984) attempted to evaluate the non-inferiority of SRT vs. WBRT specifically for EGFR-mutated non-small cell lung cancer (EGFRm NSCLC) BMs. METHODS:Inclusion criteria were ≤ 5 BMs (any size) from treatment-naïve EGFRm NSCLC. All patients started a first-generation tyrosine kinase inhibitor on the first day of WBRT (37.5 Gy/15 fractions) or SRT (25-40 Gy/5 fractions per tumor volume). The primary endpoint was 18-month intracranial progression-free survival (iPFS; intention-to-treat). RESULTS:The trial commenced in June 2015 and was closed in April 2021 after screening 208 patients but enrolling 85 (n = 41 WBRT, n = 44 SRT; median follow-up 31 and 36 months, respectively). Respectively, 9.5 % vs. 10.2 % of patients experienced intracranial progression at 18 months, and the median iPFS was 21.4 vs. 22.3 months (p > 0.05 for all). The SRT arm experienced higher overall survival and cognitive preservation (p < 0.05 for all). The most notable reason for low enrollment was patients not wishing to risk neurocognitive decline from WBRT. CONCLUSIONS:Although this phase III trial was underpowered, there was no evidence that SRT yielded outcome detriments compared to WBRT for EGFRm NSCLC BMs. Lessons from prematurely closed trials are valuable, as they often provide important experiential perspectives for investigators designing/executing future trials. In the current era, randomized trials involving WBRT without cognitive sparing measures may be at high risk of underaccrual; trial investigators are encouraged to carefully consider our experience when attempting to design such trials. However, trials of molecular-/biologically-stratified patients are highly recommended as the notion of "individualized medicine/oncology" continues to expand.

Purpose: This study aimed to combine clinical/dosimetric factors and handcrafted/deep learning radiomic features to establish a predictive model for symptomatic (grade > 2) radiation pneumonitis (RP) in lung cancer patients who received immunotherapy followed by radiotherapy.Materials and Methods: This study retrospectively collected data of 73 lung cancer patients with prior receipt of ICIs who underwent thoracic radiotherapy (TRT). Of these 73 patients, 41 (56.2 %) developed symptomatic grade >= 2 RP. RP was defined per multidisciplinary clinician consensus using CTCAE v5.0. Regions of interest (ROIs) (from radiotherapy planning CT images) utilized herein were gross tumor volume (GTV), planning tumor volume (PTV), and PTV-GTV. Clinical/dosimetric (mean lung dose and V5-V30) parameters were collected, and 107 handcrafted radiomic (HCR) features were extracted from each ROI. Deep learning-based radiomic (DLR) features were also extracted based on pre-trained 3D residual network models. HCR models, Fusion HCR model, Fusion HCR + ResNet models, and Fusion HCR + ResNet + Clinical models were built and compared using the receiver operating characteristic (ROC) curve with measurement of the area under the curve (AUC). Five-fold cross-validation was performed to avoid model overfitting.Results: HCR models across various ROIs and the Fusion HCR model showed good predictive ability with AUCs from 0.740 to 0.808 and 0.740-0.802 in the training and testing cohorts, respectively. The addition of DLR features improved the effectiveness of HCR models (AUCs from 0.826 to 0.898 and 0.821-0.898 in both respective cohorts). The best performing prediction model (HCR + ResNet + Clinical) combined HCR & DLR features with 7 clinical/dosimetric characteristics and achieved an average AUC of 0.936 and 0.946 in both respective cohorts.Conclusions: In patients undergoing combined immunotherapy/RT for lung cancer, integrating clinical/dosimetric factors and handcrafted/deep learning radiomic features can offer a high predictive capacity for RP, and merits further prospective validation.

It remains highly unclear and debatable whether combining radiotherapy (RT) and immune checkpoint blocker (ICB) therapy yields improved outcomes compared to either modality alone. Whereas some randomized data have shown improved outcomes, others have not. As a result of these conflicting data, it is essential to reconcile differences in the data and postulate reasons thereof. This work seeks to address these discrepancies, and uses the lessons learned from both positive and negative trials, including the most cutting-edge data available, in order to guide future clinical trial design and clarify the ideal/expected role of combinatorial therapy going forward. Because RT offers two distinct contributions (cytoreductive (local) effects & immune-stimulating (systemic) effects), RT should complement immunotherapy by addressing immunotherapy-resistant clones, and immunotherapy should complement RT by addressing RT-resistant or out-of-field clones. RT is not merely a single "drug", but rather a constellation of diverse "drugs" that can be varied based on dose regimens, previous systemic therapy regimens, number of irradiated sites, treatment intent/location/timing, tumor biology, and individual patient immunological circumstances. These factors are discussed as an important explanation for the discrepancies in results of various randomized trials in heterogeneous populations and clinical settings, and these discrepancies may continue until trials of more uniform circumstances are designed to use particular RT paradigms that meaningfully add value to systemic therapy.

e23262 Background: Despite the success of Immune checkpoint inhibitors (ICIs) as consolidation following concurrent chemoradiotherapy (CCRT), 22% to 30% of patients still cannot be treated with durvalumab due to progression or adverse events (AEs) during or after CCRT. Concurrent ICIs with CCRT would offer the opportunity to receive ICIs and may provide treatment benefit to a greater proportion of patients. In this study, we performed a multicenter investigation to evaluate the safety and efficacy of ICIs and chemotherapy with concurrent thoracic radiotherapy. Methods: All patients from three institutions who underwent ICIs and concurrent thoracic radiotherapy were included. The rate of 12-month progression-free survival (PFS) was estimated using the Kaplan-Meier method and evaluated with 95% CIs calculated using the Greenwood formula. Therapy-related pneumonitis (TRP) and esophagitis (TRE) were defined per CTCAE v5.0. Statistics utilized logistic regression modeling and receiver operating characteristic (ROC) analysis. Results: 69 patients (median [range] age, 62 [52-76]; 61 [88.4%] male; median follow-up 30.4 months) were collected, including 18 (26.1 %) cases of non-small cell lung cancer (NSCLC), 26 (37.7 %) cases of small cell lung cancer (SCLC), and 25 (36.2 %) cases of esophageal cancer (EC). The 12-month PFS rates in NSCLC, SCLC and EC were 72.2%, 69.2% and 72.0%, respectively. The median PFS in NSCLC and SCLC was 24.3 and 13.1 months, and not reached (mean 29 months) for EC. The incidences of all-grade TRP and TRE were 60.7% and 57.7%, respectively. Grades 1-5 TRP occurred in 15.9%, 30.4%, 8.6%, 1.4%, and 0, respectively. Grades 1-5 TRE occurred in 20.2%, 28.9%, 8.6%, 0, and 0, respectively. On multivariable analysis, age and MLD significantly predicted for any-grade and grade ≥2 TRP. Only age significantly predicted for grade ≥3 TRP. ROC analysis was able to pictorially model RP risk probabilities for a variety of MLD and age thresholds. Conclusions: This real-world study can be helpful for understanding the true efficacy and toxicity of ICIs and chemotherapy with concurrent thoracic radiotherapy given the lack of robust clinical data. Close monitoring should be recommended in this patient population during RT and follow-up.