Radiotherapy Cohort Research Articles

Survival benefit added by adjuvant chemotherapy in adenoid cystic carcinoma of salivary gland

The aim of this study was to investigate the potential survival advantages associated with chemoradiotherapy (CRT) compared to radiotherapy (RT) as standalone modalities in the treatment of adenoid cystic carcinoma (ACC) of the salivary glands. Patients diagnosed with resected salivary gland ACC were retrospectively enrolled and categorized into two groups based on the type of adjuvant therapy received. The overall survival outcomes between the CRT and RT cohorts were evaluated using a multivariable Cox model. Post propensity score-matching, a total of 114 patients (57 in each treatment group) were included in the analysis. In the general patient population, CRT did not confer an additional survival benefit compared to RT alone. High-grade tumors, positive surgical margins, and the presence of five or more positive lymph nodes were identified as independent prognostic factors associated with poorer overall survival. Specifically, for patients with positive surgical margins, CRT was significantly associated with improved overall survival relative to RT, displaying a hazard ratio of 0.93 (95% CI: 0.81–0.99). Furthermore, in patients with more than four metastatic lymph nodes, CRT significantly reduced the risk of mortality by 6% (95% CI: 1-24%) when compared to RT alone. Conversely, in patients with high-grade tumors, the addition of adjuvant chemotherapy to RT did not yield significant alterations in survival outcomes compared to RT alone (p = 0.437, HR: 0.95, 95% CI: 0.75–2.07). CRT may offer an overall survival benefit for patients with salivary gland ACC, particularly those characterized by positive margin or the presence of five or more metastatic lymph nodes.

Postprostatectomy Radiotherapy Timing and Long-Term Health-Related Quality of Life

The association between radiotherapy (RT) timing after radical prostatectomy and long-term patient-reported health-related quality of life (HRQOL) in men with prostate cancer is unknown. To measure long-term HRQOL in men with prostate cancer up to 15 years after prostatectomy with or without RT and examine whether early vs late postprostatectomy RT is associated with differences in sexual, urinary, and bowel HRQOL. A prospective, multicenter, longitudinal cohort analysis using HRQOL data from the PROST-QA (2003-2006) and RP2 consortium (2010-2013) studies was conducted. Men with localized prostate cancer undergoing radical prostatectomy were included. Data were analyzed between May 8, 2023, and March 1, 2024. The study was conducted in 12 high-volume academic medical centers in the US. Men were stratified based on receipt and timing of postprostatectomy RT: prostatectomy only, early RT (<12 months), and late RT (≥12 months). Longitudinal sexual, incontinence, urinary irritation, bowel, and hormonal/vitality HRQOL were measured via the Expanded Prostate Cancer Index Composite at baseline; months 2, 6, and 12; and annually thereafter. Treatment groups were compared using multivariable linear mixed-effects models of change in longitudinal domain scores. Pad use for incontinence was measured longitudinally among men receiving postprostatectomy RT. A total of 1203 men were included in the study: prostatectomy only (n = 1082), early RT (n = 57), and late RT (n = 64). Median age for the entire cohort was 60.5 (range, 38.8-79.7) years, and 1075 men (92.0%) were White. Median follow-up was 85.6 (IQR, 35.8-117.2) months. Compared with men receiving prostatectomy alone, those receiving postprostatectomy RT had significantly greater decreases in sexual, incontinence, and urinary irritation HRQOL. However, timing of postprostatectomy RT, specifically early vs late, was not associated with a long-term decrease in any HRQOL domain. There was evidence of improved recovery of sexual, continence, and urinary irritation scores among men receiving early RT compared with those receiving late RT after prostatectomy. Before the start of postprostatectomy RT, 39.3% of men in the early RT cohort and 73.4% of men in the late RT cohort were pad-free. By the sixth visit post-RT, 67.4% in the early RT cohort and 47.6% in the late RT cohort were pad-free. In this multicenter, prospective analysis, postprostatectomy RT appeared to be negatively associated with long-term HRQOL across all domains. However, receipt of early vs late postprostatectomy RT may result in similar long-term HRQOL outcomes.

Analysis of heterochromatin remodeling as a mechanism of radiotherapy (RT) resistance through molecular profiling of radioresistant (RR) head and neck (HNC) and prostate cancers (PCa).

137 Background: Resistance to RT remains a clinical challenge, given our limited understanding of the molecular pathways underpinning radioresistance. Here, we investigated for mechanisms linked to RR using paired experimental and clinico-molecular HNC and PCa datasets for discovery and validation of novel pathways that may be enriched in RR cancers. Methods: For experimental data, we generated RR HNC (FaDu, HK1) and PCa (22Rv1, DU145) cell lines following high-dose X-irradiation (90 Gy in 45 fr). Genotypic characterization of RR and wildtype (WT) cells was performed by genomic and transcriptomic sequencing using WES (100X) and RNAseq (Illumina, CA), respectively, followed by functional characterization by western blot (WB) and immunofluorescence (IF). For clinico-molecular data, we utilized two prospectively recruited RT cohorts, consisting of 311 patients with HNC (n=158) and PCa (n=153). Tumor transcriptomes were profiled using RNAseq and Affymetrix ST array (ThermoFisher, CA), respectively. Comparative analyses of molecular profiles were first performed between RR and WT in vitro models to identify dysregulated pathways that were linked to radioresistance, and subsequently tested for association with disease-free survival (DFS) in the clinical cohorts. Results: Comparative genomic analyses between RR and WT HNC and PCa models revealed an abundance of acquired mutations in the RR compared with WT models, with a higher mutation count observed in PCa than HNC cells (SNV counts: 2,158 [DU145-RR] and 1,387 [22Rv1-RR] vs 396 [FaDu-RR] and 25 [HK1-RR], P&lt;0.0001). Mutational signature analyses indicated a common enrichment of DNA mismatch repair-related mutational signatures (SBS3, SBS14, and SBS21) across the RR HNC and PCa models. Transcriptomic profiling revealed an upregulation of the BAHD1 gene, which is involved in heterochromatin formation, across the 4 RR cell lines, corroborated by an enrichment of heterochromatin-related genesets. These results were consistent with functional characterization of RR versus WT cells by WB and IF indicating increased DNA repair capacity and heterochromatin response post-4 Gy irradiation. We further confirmed the dependency of the RR phenotype on the heterochromatin response with BAHD1 knockdown, resulting in reversal of these cellular responses. Finally, our results were supported by survival analyses indicating an inferior DFS post-RT in patients with HNC and PCa harboring a higher expression of heterochromatin-related geneset (HNC: HRhigh vs low 1.51 ; PCa: HRhigh vs low 1.37 ). Conclusions: Herein, by leveraging on paired experimental and clinico-molecular datasets, we have uncovered a novel BAHD1-dependent heterochromatin response that underpins resistance to RT in HNC and PCa, which may be amendable to systemic agents targeting chromatin remodeling.

Clinical analysis of the efficacy of radiation therapy for primary high-grade gliomas guided by biological rhythms

ObjectiveHigh-grade glioma (HGG) patients frequently encounter treatment resistance and relapse, despite numerous interventions seeking enhanced survival outcomes yielding limited success. Consequently, this study, rooted in our prior research, aimed to ascertain whether leveraging circadian rhythm phase attributes could optimize radiotherapy results. MethodsIn this retrospective analysis, we meticulously selected 121 HGG cases with synchronized rhythms through Cosinor analysis. Post-surgery, all subjects underwent standard radiotherapy alongside Temozolomide chemotherapy. Random allocation ensued, dividing patients into morning (N = 69) and afternoon (N = 52) radiotherapy cohorts, enabling a comparison of survival and toxicity disparities. ResultsThe afternoon radiotherapy group exhibited improved overall survival (OS) and progression-free survival (PFS) relative to the morning cohort. Notably, median OS extended to 25.6 months versus 18.5 months, with P = 0.014, with median PFS at 20.6 months versus 13.3 months, with P = 0.022, post-standardized radiotherapy. Additionally, lymphocyte expression levels in the afternoon radiation group 32.90(26.10, 39.10) significantly exceeded those in the morning group 31.30(26.50, 39.20), with P = 0.032. ConclusionsThis study underscores the markedly prolonged average survival within the afternoon radiotherapy group. Moreover, lymphocyte proportion demonstrated a notable elevation in the afternoon group. Timely and strategic adjustments of therapeutic interventions show the potential to improve therapeutic efficacy, while maintaining vigilant systemic immune surveillance. A comprehensive grasp of physiological rhythms governing both the human body and tumor microenvironment can refine treatment efficacy, concurrently curtailing immune-related damage—a crucial facet of precision medicine.

Abstract PS18-02: Prevalence of Refusal of Recommended Cancer Treatments and Survival Differences in Breast Cancer Patients: Analysis of the National Cancer Database

Abstract Background: Some breast cancer patients (pts) refused treatment despite their providers’ recommendations. Treatment refusals can be detrimental to these pts’ short- and long-term health outcomes. Limited research has investigated the national trends in treatment refusals and their impacts on the survival of breast cancer pts. Methods: We analyzed data collected from breast cancer pts in the 2004-2020 National Cancer Database (NCDB). Four treatment modalities were assessed: chemotherapy (CT), hormone therapy (HT), radiotherapy (RT), and surgery. The CT cohort included stage I-IV pts. The HT cohort included stage I-IV, hormone receptor-positive pts. The RT or surgery cohort was limited to only stage I-III pts. Refusal status was categorized as “yes/no,” and its correlates were assessed using multivariable logistic regression. Estimated rates of overall survival (OS) were calculated using the Kaplan-Meier method. The association between refusal status and OS was examined using log-rank tests, followed by multivariable Cox regression models. Results: In the CT cohort, 9.6% of 1,296,488 pts who were offered the treatment refused. In the RT cohort, 6.1% of 1,635,916 pts refused. In the HT cohort, 5.0% of 1,893,339 pts refused. In the surgery cohort, only 0.6% of 2,590,963 pts refused. Significant increasing trends in treatment refusals from 2004-2020 across the four treatment modalities were observed (all p-trends &amp;lt; .001). We found significant differences in age, race, AJCC stage group, molecular subtype, tumor grade, and care access indicators (e.g., insurance, median household income, facility type, and rural/urban area) by refusal status. Black pts were more likely than White pts to refuse surgery (adjusted odds ratio [AOR] 2.01, 95% CI: 1.89-2.14). Asian or Pacific Islander pts were also more likely to refuse surgery (AOR 1.29, 95% CI: 1.15-1.44) and CT (AOR 1.21, 95% CI: 1.16-1.27). Uninsured pts were more likely than privately insured pts to refuse surgery (AOR 4.83, 95% CI: 4.22-5.51), RT (AOR 1.97, 95% CI: 1.83-2.12), CT (AOR 1.61, 95% CI: 1.51-1.72), and HT (AOR 1.61, 95% CI: 1.49-1.73). Compared with pts who did not refuse treatment, those who refused had lower rates of 5-year OS in the cohorts of HT (81.4% vs. 88.4%), CT (74.9% vs. 84.4%), RT (74.4% vs. 90.8%), and surgery (42.0% vs. 88.1%). When stratified by stage, similar patterns of 5-year OS rates were observed across all cohorts. After adjusting for sociodemographic and clinicopathologic factors, pts who refused surgeries had a higher mortality risk than those who did not (aHR 2.91, 95% CI: 2.82-3.01). Pts who refused RT had a higher risk of dying than those who did not (aHR 1.97, 95% CI: 1.93-2.01). Pts who refused CT had a greater risk of dying than those who did not (aHR 1.86, 95% CI: 1.83-1.90). Pts who refused HT had a greater risk of death than those who did not (aHR 1.56, 95% CI: 1.53-1.59). Black pts had higher mortality risk than their White counterparts across all cohorts (HT: aHR 1.15, 95% CI: 1.13-1.17; CT: aHR 1.14, 95% CI: 1.12-1.16; RT: aHR 1.11, 95% CI: 1.1.09-1.14; surgery: aHR 1.10, 95% CI: 1.08-1.11). Conclusions: In this sample of breast cancer pts, the rate of treatment refusal was highest for CT and lowest for surgery, and there were significantly increased trends in refusals over time. Age, race, stage, molecular subtype, tumor grade, and care access measures were independently associated with treatment refusals, suggesting that differential refusals not only are affected by biological factors but also may reflect disparities in socioeconomic status. Furthermore, pts who refused treatment experienced worse OS, regardless of treatment modality. These findings suggest that stressing the importance of recommended treatment and interventions tailored for this patient population may be needed to improve their survival outcomes. Citation Format: Jincong Freeman, James Li, Susan Fisher, Katharine Yao, Sean David, Dezheng Huo. Prevalence of Refusal of Recommended Cancer Treatments and Survival Differences in Breast Cancer Patients: Analysis of the National Cancer Database [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS18-02.

Abstract PO3-22-05: Investigating HER2-low tumors from a locoregional perspective- a secondary analysis of a randomized radiotherapy trial

Abstract Background: With the introduction of antibody-drug conjugates directed against HER2, a new subgroup of tumors with low HER2 expression (1+ or 2+ without amplification) has emerged. HER2 signaling has been implicated in radioresistance in mechanistic studies and is an accepted biomarker of immunogenicity. The study aimed to contrast tumors with low HER2 expression versus zero HER2 expression from a prognostic and radiotherapy-predictive locoregional perspective. Methods: HER2 status was evaluated using immunohistochemistry and SISH in the randomized radiotherapy (RT) cohort, SweBCG91RT, by a board-certified pathologist. HER2-low status was defined as HER2 IHC 1+ or 2+ without amplification, HER2-zero as 0, and HER2-high as HER2 IHC 3+ or SISH amplified. Tumor-infiltrating lymphocytes were assessed on whole-tissue sections and categorized as low (&amp;lt; 10%) or high (≥ 10%). The endpoint was time to ipsilateral breast tumor recurrence (IBTR) as first event. Results: Out of 964 evaluated primary tumors, 433 (44.9%) were classified as HER2-low, 467 (48.4%) as HER2-zero and 64 (6.6%) as HER2-high. TILs levels did not differ between HER2-low and HER2-zero tumors (p=0.33). The hazard ratio for high TILs was 0.79 in HER2-zero tumor (CI 95% 0.43-1.45, p=0.44) and 0.96 in HER2-low tumor (CI 95% 0.56-1.66, p=0.90), and no interaction effect from TILs was observed (p=0.63). The benefit from RT was similar among HER2-low (HR 0.42, CI 95% 0.25-0.72, p=0.001) and HER2-zero tumors (HR 0.31, CI 95% 0.17-0.56, p&amp;lt; 0.001). Conclusions: HER2-low tumors do not differ from HER2-zero tumors regarding the benefit from postoperative RT. Unlike high HER2 expression, low expression is not associated with TILs infiltration. HER2-low tumors likely do not represent a biologically distinct subtype from a locoregional aspect. Citation Format: Per Karlsson, Anikó Kovács, Fredrika Killander, Emma Niméus, Erik Holmberg, Axel Stenmark Tullberg. Investigating HER2-low tumors from a locoregional perspective- a secondary analysis of a randomized radiotherapy trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-22-05.

Abstract 1123: Genomic characterization of radiotherapy-associated bladder cancer

Abstract Background: Bladder cancer (BCa) is the 4th most common cancer diagnosed in men, with 82,290 new cases predicted in 2023. As BCa frequently occurs at an advanced patient age, its diagnosis may follow radiotherapy (RT) for the treatment of prostate cancer. Currently, data is limited regarding the influence of RT on the clinical course and genomic landscape of subsequent BCa, mainly due to a paucity of samples. From prior studies, pelvic radiation confers an increased risk of BCa, with resulting tumors that are largely genomically similar to non-RT tumors with the exception of an increase rate of genomic insertions. Our current study looks to expand on these findings by characterizing the genomes of the largest cohort of RT-associated bladder cancers to date. Methods: We identified BCa cases from patients with a prior history of pelvic radiation for prostate cancer, and tumor only targeted sequencing was performed using Foundation Medicine (FMI) on FFPE tissue (n=41). For control cases (CTRL), patients with no prior record of pelvic radiation and who had previously underwent standard of care FMI sequencing were included (n=41). Sequencing data were re-aligned to hg38 and mutation calling was performed on the newly aligned sequences. Results: CTRL and RT cohorts had similar distributions of patients based on race and smoking status. While cT stage was similar between the two cohorts, the CTRL cohort was biased toward higher cN and cM stages with no difference in overall survival (median OS: CTRL = 20m, RT = 23m), though the advanced stage of the CTRL cohort could mask a worse prognosis in the RT cohort. Latency specific analysis revealed short latency tumors (&amp;lt;10 years from RT) had a significantly shorter overall survival than long latency tumors (p&amp;lt;0.01, HR=5.59, CI=1.81-17.3), and a numerically, but not significantly, shorter survival than CTRL patients (p=0.17, HR=1.55, CI=0.82-2.94). Long latency tumor patients had a significantly longer overall survival than CTRL patients (p&amp;lt;0.01, HR = 0.22, CI=0.07-0.63). In line with prior studies, RT samples had increased numbers of insertions (p&amp;lt;0.01). In addition, we also detected an increase in SNVs in the RT samples (p&amp;lt;0.01). Of note, KDM6A alterations were enriched within the RT cohort (CTRL = 10/41, RT = 30/41, p&amp;lt;0.001), with series of splice site mutations exclusive to RT samples (p&amp;lt;0.001). Conclusion: Patients diagnosed with BCa within a short interval following pelvic radiation have a worse prognosis. Genomic analysis showed RT-associated tumors having an increased number of insertions, SNVs, and KDM6A splice site mutations compared to non-RT tumors. Overall, the spectrum of recurrent alterations within the cohorts were consistent with previous studies, with the exception of the KDM6A mutations. To our knowledge, this is the first report of a RT-associated alteration in a specific gene in bladder cancer and additional studies will be needed to validate and understand the consequences of this finding. Citation Format: N. Ari Wijetunga, Kathryn H. Gessner, Krishna Kanchi, Sara E. Wobker, David Corcoran, Matthew D. Galsky, Matthew I. Milowsky, William Y. Kim, Tracy L. Rose, Jeffrey S. Damrauer. Genomic characterization of radiotherapy-associated bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1123.

Risk of thoracic soft tissue sarcoma after breast cancer radiotherapy: a population-based cohort study in Osaka, Japan.

Postoperative radiotherapy for breast cancer reportedly increases the risk of thoracic soft tissue sarcomas, particularly angiosarcomas; however, the risk in the Japanese population remains unknown. Therefore, this study aimed to investigate the incidence of thoracic soft tissue sarcoma among patients with breast cancer in Japan and determine its association with radiotherapy. This retrospective cohort study used data from the population-based cancer registry of the Osaka Prefecture. The inclusion criteria were female sex, age 20-84years, diagnosis of breast cancer between 1990 and 2010, no supraclavicular lymph node or distant metastasis, underwent surgery and survived for at least 1year. The primary outcome was the occurrence of thoracic soft tissue sarcomas 1year or later after breast cancer diagnosis. Among the 13 762 patients who received radiotherapy, 15 developed thoracic soft tissue sarcomas (nine angiosarcomas and six other sarcomas), with a median time of 7.7years (interquartile range, 4.0-8.6years) after breast cancer diagnosis. Among the 27 658 patients who did not receive radiotherapy, four developed thoracic soft tissue sarcomas (three angiosarcomas and one other sarcoma), with a median time of 11.6years after diagnosis. The 10-year cumulative incidence was higher in the radiotherapy cohort than in the non-radiotherapy cohort (0.087 vs. 0.0036%, P < 0.001). Poisson regression analysis revealed that radiotherapy increased the risk of thoracic soft tissue sarcoma (relative risk, 6.8; 95% confidence interval, 2.4-24.4). Thus, although rare, breast cancer radiotherapy is associated with an increased risk of thoracic soft tissue sarcoma in the Japanese population.

PET/CT-Based Radiogenomics Supports KEAP1/NFE2L2 Pathway Targeting for Non-Small Cell Lung Cancer Treated with Curative Radiotherapy.

In lung cancer patients, radiotherapy is associated with a increased risk of local relapse (LR) when compared with surgery but with a preferable toxicity profile. The KEAP1/NFE2L2 mutational status (MutKEAP1/NFE2L2) is significantly correlated with LR in patients treated with radiotherapy but is rarely available. Prediction of MutKEAP1/NFE2L2 with noninvasive modalities could help to further personalize each therapeutic strategy. Methods: Based on a public cohort of 770 patients, model RNA (M-RNA) was first developed using continuous gene expression levels to predict MutKEAP1/NFE2L2, resulting in a binary output. The model PET/CT (M-PET/CT) was then built to predict M-RNA binary output using PET/CT-extracted radiomics features. M-PET/CT was validated on an external cohort of 151 patients treated with curative volumetric modulated arc radiotherapy. Each model was built, internally validated, and evaluated on a separate cohort using a multilayer perceptron network approach. Results: The M-RNA resulted in a C statistic of 0.82 in the testing cohort. With a training cohort of 101 patients, the retained M-PET/CT resulted in an area under the curve of 0.90 (P < 0.001). With a probability threshold of 20% applied to the testing cohort, M-PET/CT achieved a C statistic of 0.7. The same radiomics model was validated on the volumetric modulated arc radiotherapy cohort as patients were significantly stratified on the basis of their risk of LR with a hazard ratio of 2.61 (P = 0.02). Conclusion: Our approach enables the prediction of MutKEAP1/NFE2L2 using PET/CT-extracted radiomics features and efficiently classifies patients at risk of LR in an external cohort treated with radiotherapy.

Does use of apalutamide enhance outcomes in combination with radiotherapy in metastatic hormone-sensitive prostate cancer? A real-world experience from the UK.

73 Background: Management of metastatic prostate cancer has undergone a significant change over the past decade, with the introduction of several novel agents and repurposing of others. Latest update from STAMPEDE trials shown prostate radiotherapy (RT) improves OS, without detriment in QoL in metastatic home sensitive prostate cancer mHSPC along with Docetaxel in those with low volume metastatic disease. There is no published data on impact of radiotherapy to prostate on Apalutamide treated mHSPC patients. Here we report our real-world experience of Apalutamide in mHSPC with radiotherapy. Methods: Patients with mHSPC (N = 266) from 5 UK centres, were treated with Apalutamide (240 mg) and ADT along with radiotherapy to prostate as per treating clinician’s discretion. The primary endpoint was objective rate (ORR) as determined by patients achieving a PSA decline of ≥90% (PSA90) and ≥50% (PSA50) and secondary endpoints included biochemical progression free survival (bPFS) and safety. Results: The median age for the whole cohort was 73.4 years (interquartile range 52 - 91), A total of 11.6% had received prior radical treatment (prostatectomy or radiotherapy for localised disease) and 88.4% had de novo metastatic disease. Median baseline PSA was 47 ng/ml (range 0.4-17100). The proportion of patients PSA90 and PSA50 at 3, 6 and 12 months is shown in the Table. Median PSA nadir was 0.1 ng/ml(rage 0.01- 48.2) and median time to reach nadir was 6 months (range 3-24 months). 13.5% (35) patients were treated with radiotherapy (RT) after at least 3 months (range 3 -6 months) of starting apalutamide. Patients received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) of radiotherapy (68 % vs 32%). Higher number of patients in RT group had achieved PSA90 compared to no radiotherapy cohort (97.14 % vs 87.3%, p =0.15). Patients treated with RT had median post treatment of PSA 0.01 ng/ml compared to 0.1 ng/ml in non RT group (p=0.0062). After median follow up of 8.4 months, proportion of patients shown biochemical progression in RT vs non RT group were 5.7 % vs 15 % respectively (p= 0.04). Patients with de novo metastatic disease have shown poor PSA response and higher chance of progression compared to patients who had initial radical treatment. Radiotherapy was well tolerated, with 17 % adverse events (Radiation Therapy Oncology Group grade 3–4) reported in radiotherapy group. Conclusions: Early experience of using apalutamide and radiotherapy in mHSPC showed improved PSA response and delayed progression. Treatment was well tolerated. Further follow up and clinical trials are needed to understand the impact on overall survival. [Table: see text]

Two distinct age-prognosis patterns in patients with esophageal cancer undergoing surgical and radiotherapy treatments: a combined analysis of 3JECROG and SEER databases.

Age is a known prognostic factor for various cancers. However, few studies explored the association between age and prognosis of esophageal cancer (EC) comprehensively, especially from a nonlinear perspective. Retrospective cohort study. Our study aims to explore the possible nonlinear associations between age and prognosis in EC patients receiving curative surgery and radiotherapy, respectively. Cox regression models with restricted cubic splines were used to model the possible nonlinear relationship between age and prognosis in surgical and radiotherapy groups, respectively. Surveillance, Epidemiology, and End Results database was used to validate the age-prognosis patterns found in Jing-Jin-Ji Esophageal and Esophagogastric Cancer Radiotherapy Oncology Group database. Age-prognosis patterns were further validated by survival comparisons between different age subgroups and in subsequent sensitivity and subgroup analyses. Primary endpoint is overall survival. Secondary endpoints are cancer-specific survival and progression-free survival. A total of 56,457 patients from two large cancer databases were included. Patients receiving surgery and radiotherapy showed two distinct nonlinear age-prognosis patterns. Age showed a U-/J-shaped association with prognosis in the radiotherapy group, with a nadir at approximately 65- to 70-years-old. As for surgical cohort, relative risk for all-cause mortality and cancer-specific mortality increased with age with p for nonlinearity <0.05. The above age-prognosis relationships were validated by sensitivity, subgroup, and comparative survival analyses. Youngest and middle-aged patients showed better survival results compared to that of other age subgroups in surgical and radiotherapy cohorts, respectively [Radiotherapy, youngest/middle: hazard ratio (HR) = 1.06, 95% confidence interval (CI): 1.02-1.10, p = 0.001; Radiotherapy, oldest/middle: HR = 1.21, 95% CI: 1.18-1.24, p < 0.001; Surgical, middle/youngest: HR = 1.19, 95% CI: 1.14-1.25, p < 0.001; surgical, oldest/youngest: HR = 1.85, 95% CI: 1.75-1.97, p < 0.001]. Patients receiving surgery and radiotherapy showed two distinct age-prognosis patterns. Younger and middle-aged patients were associated with better survival in surgical and radiotherapy groups, respectively. Additional studies are warranted to explore the underlying mechanisms and clinical implications of this phenomenon.

Radiotherapy with or without immunotherapy in metastatic melanoma: efficacy and tolerability

Introduction Radiotherapy (RT) is primarily considered as a palliative treatment in patients with metastatic melanoma. However, observations suggest that when RT is combined with immune checkpoint inhibitors (ICI), it can induce an immune response leading to an anti-tumoral effect also distant from the irradiated area – a phenomenon called ‘abscopal effect’. The frequency and circumstances of abscopal effect among metastatic melanoma patients remains uncertain and further research is necessary. Material and method This retrospective study included all metastatic melanoma patients who received non-stereotactic RT in Stockholm, Sweden in 2015–2020. Patients were grouped depending on if RT was given at start of ICI (RT + ICI(start)), at ICI progression (RT + ICI(salvage)) or without ICI (RT(only)). Response rates in irradiated (RR(irradiated)) and overall response rates in non-irradiated (ORR(non-irradiated)) metastases were evaluated together with survival and toxicity in each cohort. Results In the RT + ICI(start) (n = 47), RT + ICI(salvage) (n = 41) and RT(only) (n = 55) cohorts, RR(irradiated) was 70.7%, 67.5% and 43.1% (p = 0.018) while the ORR(non-irradiated) was 36.1%, 14.8% and 0.0% (p = 0.003), and the median overall survival was 18.2, 15.0 and 7.2 months, respectively (p = 0.014). Local response to RT was in all cohorts associated with longer survival (p < 0.001). The frequency of grade ≥3 immune-related adverse events was 17.0% and 19.5% in the RT + ICI(start) and RT + ICI(salvage) cohorts. No increased frequency of RT-related adverse events was seen in the RT + ICI cohorts, compared to the RT(only) cohort. Conclusion This retrospective study showed that melanoma patients receiving RT in combination with ICI had a superior antitumoral response in both irradiated and non-irradiated lesions as compared to patients receiving only RT. Additionally, a subgroup of patients receiving RT when progressing on ICI experienced tumor regression also in non-irradiated areas.

NIMG-16. THE PROGNOSTIC VALUE AND BIOLOGICAL SIGNIFICANCE OF MRI CE-T1-BASED RADIOMICS MODELS IN CNS5-IDENTIFIED GBM

Abstract BACKGROUND Following the publication of the 2021 WHO Classification of CNS Tumors (Fifth Edition) (CNS5), prognostic markers to guide the individualized treatment of patients with glioblastoma (GBM) (CNS5) need to be explored. Radiomics is a non-invasive, reproducible, and cost-effective method that has been used in the prognostic assessment of multiple solid tumors. The prognostic value and biological significance of MRI T1 - weighted enhancement (CE-T1) - based radiomics models in GBM (CNS5) has not been reported. METHODS The tumor region of MRI CE-T1 phase was segmented, and radiomics features were extracted. The consistency analysis, univariate Cox regression and two machine learning algorithms were used for feature reduction. Then, the radiomics prognostic model was established to calculated the radiomics score (RS). The independent external validation was independently verified using the bicenter radiotherapy cohorts. The enrichment analyses of the differential genes between RS-high and -low groups were implemented to explore the biological significance. RESULTS A prognostic model composed of six radiomics features were built. A high RS (HR=3.718, 95%CI: 2.222−6.220, P&amp;lt; 0.001) was an independent risk factor for overall survival (OS). The result was externally validated by two cohorts. Through biological significance exploration, RS was found to be significantly correlated with DNA repair (P=0.009) and glycolysis (P=0.001) pathway enrichment scores. RS was associated with γδT cell infiltration and the expression of LAG3. CONCLUSION The MRI CE-T1 based radiomics prognostic models constructed can predict GBM (CNS5) prognosis noninvasively and effectively, which is relevant to DNA repair, and may guide the screening of radiosensitive populations.

Radiotherapy Consolidation Reduces Risk of Relapse in Diffuse Large B-Cell Lymphoma Patients with Bulky Disease in Complete Response after Frontline Immunochemotherapy: Results from a Retrospective Single Center Study

INTRODUCTION: The role of radiotherapy (RT) consolidation upfront in patients with diffuse large B-cell lymphoma (DLBCL) and bulky disease at diagnosis is controversial, especially in those in complete response (CR) after immunochemotherapy. METHODS: All patients with DLBCL diagnosed between January 2010 and June 2021 at AOU Città della Salute e della Scienza di Torino and treated frontline with RCHOP-like regimens were retrospectively selected. Patients with primary mediastinal lymphoma were excluded. Clinical and biological features as well as treatment and survival data for the whole population were collected. All patients with bulky disease (defined as ≥6 cm) at diagnosis who obtained CR (defined as PET/TC Deauville score ≤ 3) at the end of systemic treatment were further selected. Progression free survival (PFS) and overall survival (OS) were compared between patients receiving consolidative RT on initial bulky mass and those who did not. RESULTS: A total of 453 patients with DLBCL were identified. Median age was 68 years (IQR 58-77), 56% were males, 74% stage ≥3, 52% IPI ≥3. 140/451 (31%) had bulky disease at diagnosis. Median follow-up was 5 years. 5-year PFS and OS for the whole cohort were 59% and 66%, respectively. Bulky disease correlated with a significantly lower 5-year PFS (bulky 50% vs no bulky 64%, p = 0.0005) and OS (bulky 68% vs no bulky 60%, p = 0.01). 82 out of 140 patients with bulky disease (68/82 with a bulky ≥7 cm) were in CR after immunochemotherapy: 19/82 (23%) received RT (16/19 on bulky ≥7 cm), 63/82 (77%) did not (55/63 with a bulky ≥7 cm). There were no significant differences between the two groups regarding age, stage, ECOG PS, LDH levels, extranodal involvement and IPI. RT dose was 30 Gy in most patients (17/19); two patients received 36 Gy and 40 Gy. The 5-year PFS was 95% in the RT cohort and 58% in the no-RT cohort (p = 0.004); the 5-y OS was 95% in the RT cohort and 69% in the no-RT cohort (p = 0.038) (figure 1). A propensity score matching analysis confirmed the benefit of RT on PFS (HR 0.1, 95% CI 0.01-0.68, p = 0.019), and showed a non-statistically significant trend of better OS (p = 0.06). 14/24 relapses in the no-RT cohort occurred on the site of bulky disease. CONCLUSIONS: With the limit of a non-randomized retrospective study, our data showed a benefit of RT consolidation on bulky disease in patients with DLBCL in RC after frontline immunochemotherapy, significantly prolonging PFS and with a trend of improved OS in a propensity score matching analysis.

Dynamics of Radiomic Features Following Bridging Therapy Determine CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy Outcome

Introduction: Greater burden of disease is associated with poorer outcomes after CAR T therapies. Bridging therapy (BT) is widely used to debulk or palliate between apheresis and CAR T infusion. We studied whether the degree and dynamics of radiomic cytoreduction during the bridging period are prognostic. Methods: Patients with large B-cell lymphoma (LBCL) treated with CD19 CAR T from 2016-2022 were stratified into 3 BT cohorts: 1) no BT 2) radiotherapy (RT) or 3) systemic therapy (ST) including combined ST+RT. All patients had a pre-apheresis PET. Patients in the RT or ST cohorts also had a repeat PET post-BT but pre-CAR T infusion. Radiomic parameters of interest including max SUV and metabolic tumor volume (MTV) were calculated for all scans. MTV was determined using a semi-automated method and SUV4 threshold. Max SUV and MTV pre- and post-BT were compared using Wilcoxon signed-rank tests. Kaplan Meier was used to calculate progression free survival (PFS) and overall survival (OS) from CAR T infusion; univariable and multivariable analysis were performed by Cox proportional hazards. Patients were stratified by disease burden using an absolute MTV cutpoint established based on pre-BT PET with a maximally selected log-rank statistic for PFS via the maxstat package in R. “High” and “low” MTV were defined as MTV above or below this cutpoint, respectively. To quantify the impact of effective cytoreduction during BT, we created 4 BT MTV risk groups: a) “Low” with low MTV pre and post BT, b) “High” with high MTV pre and post BT, c) “Rising” with baseline low MTV which increased to high post BT and d) “Improved” with baseline high MTV which decreased to low post BT. Results: 158 patients with LBCL (79%), high grade BCL (17%) or primary mediastinal BCL (4%) received CAR T (51% axicabtagene, 28% tisagenlecleucel, 21% lisocabtagene). 42 (27%) received no BT, 93 (59%) had ST, 23 (15%) had RT. With median follow-up of 28.6 months, 12- and 24-month PFS were 43% and 36% and OS were 68% and 54%, respectively. Median pre-BT SUV max was 19 (range: 0-47) which reduced significantly to 13 post-BT (p&amp;lt;0.001). Median baseline MTV was 55cc (0-2,278) which reduced 40% to 33cc post-BT (p=0.001). Of the 116 patients who received BT, 67% had any degree of quantitative cytoreduction post-BT and only 35% achieved at least 50% MTV reduction [Fig A]. In the RT bridged 2yr PFS was 52% (95% CI: 32-83) vs. No BT (37%, 95% CI: 24-56) or ST bridged (33%, 95% CI: 24-45). Our established MTV cutoff was 35.5cc and was significantly associated with PFS both pre-BT and post-BT. The MTV dynamics during BT were further prognostic [Fig B] with best PFS seen in the Low risk group (1yr PFS: 73%) and worst in the High risk (1yr PFS: 21%) and Rising risk groups. In contrast, despite high baseline MTV, the Improved risk group had comparatively better outcomes with 1yr PFS of 52%. In a multivariable model of the 116 patients who had BT, several factors were associated with poorer PFS including higher pre-BT LDH (HR 2.2, p=0.004) and BT MTV risk grouping (p&amp;lt;0.001). Of note, while the High risk group had significantly worse PFS vs. Low risk (HR 4.7, 95% CI: 2.1-10.5) outcomes for the Improved risk group did not differ significantly from Low risk (HR 2.1, 95% CI: 0.8-5.3). Conclusions: In our real-world experience, while most patients required BT, many did not achieve successful disease cytoreduction prior to CAR T cells. While disease extent both pre-apheresis and post-BT are prognostic, the quantitative dynamics of BT cytoreduction may further refine prognostic ability. BT responders have better outcomes while stably high or rising MTV through BT is associated with poor prognosis.

Development of Population-Based Pediatric Computational Phantoms for Radiotherapy Applications.

Age-specific pediatric computational phantoms are used in radiotherapy (RT) for quality assurance and for reconstruction of historical RT doses (within others). Phantoms are typically developed from healthy patients and may not effectively represent those with cancer due to pathology and/or treatment effects. This study evaluated a set of population-based pediatric computational phantoms developed in-house in terms of anatomical plausibility. Planning CTs and contours from historical craniospinal irradiation (CSI) patients (n = 74, median age 7y, range: 1-17y) were used to generate and evaluate a set of in-house age-specific population-based RT phantoms (RT-P). The RT-P were generated by combining a sub-set of clinical CTs and contours through groupwise deformable image registration, generating average models of CSI sub-populations (n = 74, median age 7y, range: 3-14y). Models were then compared against clinical data and two libraries of phantoms representing healthy populations: the International Commission on Radiological Protection (ICRP) pediatric reference computational phantoms (n = 8, median age 8y, range: 1-15y) and a variety of default 4D extended cardiac torso (XCAT) phantoms (n = 75, median age 9y, range: 1-18y). Variation between organ volumes for the different datasets was assessed through a linear fit of organ volume with age, reporting the slope (∑) of each fit [y-1]. Average difference between the volume datapoints and the linear fit for clinical data (Δ) [%] were also reported. This allowed for comparisons of the RT-P to clinical and reference data in terms of organ volumes across developmental stages. The table shows 9 of the 19 investigated organs. The ∑ reported for RT-P models were of similar magnitude as the clinical data and other phantoms, effectively modelling changes with age. The greatest and least ∑ were reported from lungs and thyroid respectively, in agreement with expected relative sizes between organs. Larger values for Δ were likely due to differences in organ filling and segmentation strategy between datasets, limitations of RT-P methodology, and/or anatomical differences between healthy and cancer populations. The RT-P models show promise in representing the RT cohort that may benefit from specialized anatomical phantoms. Further work is needed to address the limitations of the current methodology and its applicability to other RT cohorts.

Imaging Performance of the PET Scan on a Novel Ring Gantry-Based PET/CT Linear Accelerator System in the First-in-Human Study of Biology-Guided Radiotherapy

Biology-guided radiotherapy (BgRT) is a novel tracked dose delivery modality using real-time positron emission tomography (PET) to guide radiotherapy beamlets. The present study was performed with sequential cohorts of participants to evaluate the performance and safety of BgRT. Primary endpoints were previously reported. We hereby report on one of the secondary endpoints assessing a novel treatment planning machine with integrated dual kVCT/PET imaging ("novel device") performance in comparison to a third-party diagnostic PET/CT scan. This single-arm, open-label, prospective study included participants with at least 1 FDG-avid targetable primary or metastatic tumor (≥2cm and ≤5cm) in the lung or bone. PET imaging data were collected on the novel device and on a third-party diagnostic PET/CT performed in sequence once at the planning timepoint in Cohort I, and immediately before the last fraction among patients undergoing stereotactic radiotherapy in Cohort II. Three central read radiation oncologists (CRRO) provided an interpretation of the novel device PET scans which were compared to an agreement standard based on 3 central radiologists' review of the paired diagnostic PET/CT scan. Positive percent agreement for localization of the target tumor within the biology-tracking zone (BTZ) was the key metric because it reflects whether advancing patients to subsequent steps in the BgRT workflow based on the novel device's imaging was ultimately appropriate. In Cohort 1, 6 image comparisons were performed. The positive (%) agreement for the aggregate radiation oncologist review was 100% (5/5), reflecting that in all 5 cases where the aggregate radiation oncologists deemed the tumor to fall within the BTZ based upon the novel device PET images, the central radiologists came to the same conclusion upon review of the paired diagnostic PET/CT images. The overall (%) agreement for the aggregate radiation oncologist review was 83.3% (5/6): localization was not established on the novel device in 1 case, even though it was established on the diagnostic PET/CT. This would not pose risk in real world practice as BgRT candidacy would be aborted for tumors not visible on the novel device. In Cohort II, among the 7 image comparisons, there was 100% positive percent agreement between the aggregate CRRO and the agreement standard as the localization criteria was met in both scans for all 7 patients. This was concordant with a 100% overall percent agreement. This investigation demonstrated a 100% positive percent agreement between central review of this novel device images by radiation oncologists and central review of the accompanying third-party PET/CT images by radiologists. There were no cases where a positive localization by the aggregate CRRO was not confirmed by the third-party PET/CT standard, providing evidence against the likelihood of falsely positive localizations on the novel device that would inappropriately advance patients in the workflow.

Biochemical Recurrence and Risk of Mortality Following Radiotherapy or Radical Prostatectomy

Stratifying patients with biochemical recurrence (BCR) after primary treatment for prostate cancer based on the risk of prostate cancer-specific mortality (PCSM) is essential for determining the need for further testing and treatments. To evaluate the association of BCR after radical prostatectomy or radiotherapy and its current risk stratification with PCSM. This population-based cohort study included a total of 16 311 male patients with 10 364 (64%) undergoing radical prostatectomy and 5947 (36%) undergoing radiotherapy with curative intent (cT1-3, cM0) and PSA follow-up in Stockholm, Sweden, between 2003 and 2019. Follow-up for all patients was until death, emigration, or end of the study (ie, December 31, 2018). Data were analyzed between September 2022 and March 2023. Primary outcomes of the study were the cumulative incidence of BCR and PCSM. Patients with BCR were stratified in low- and high-risk according to European Association of Urology (EAU) criteria. Radical prostatectomy or radiotherapy. A total of 16 311 patients were included. Median (IQR) age was 64 (59-68) years in the radical prostatectomy cohort (10 364 patients) and 69 (64-73) years in the radiotherapy cohort (5947 patients). Median (IQR) follow-up for survivors was 88 (55-138) months and 89 (53-134) months, respectively. Following radical prostatectomy, the 15-year cumulative incidences of BCR were 16% (95% CI, 15%-18%) for the 4024 patients in the low D'Amico risk group, 30% (95% CI, 27%-32%) for the 5239 patients in the intermediate D'Amico risk group, and 46% (95% CI, 42%-51%) for 1101 patients in the high D'Amico risk group. Following radiotherapy, the 15-year cumulative incidences of BCR were 18% (95% CI, 15%-21%) for the 1230 patients in the low-risk group, 24% (95% CI, 21%-26%) for the 2355 patients in the intermediate-risk group, and 36% (95% CI, 33%-39%) for the 2362 patients in the high-risk group. The 10-year cumulative incidences of PCSM after radical prostatectomy were 4% (95% CI, 2%-6%) for the 1101 patients who developed low-risk EAU-BCR and 9% (95% CI, 5%-13%) for 649 patients who developed high-risk EAU-BCR. After radiotherapy, the 10-year PCSM cumulative incidences were 24% (95% CI, 19%-29%) for the 591 patients in the low-risk EAU-BCR category and 46% (95% CI, 40%-51%) for the 600 patients in the high-risk EAU-BCR category. These findings suggest the validity of EAU-BCR stratification system. However, while the risk of dying from prostate cancer in low-risk EAU-BCR after radical prostatectomy was very low, patients who developed low-risk EAU-BCR after radiotherapy had a nonnegligible risk of prostate cancer mortality. Improving risk stratification of patients with BCR is pivotal to guide salvage treatment decisions, reduce overtreatment, and limit the number of staging tests in the event of PSA elevations after primary treatment.

Survival After Cryotherapy Versus Radiotherapy in Low and Intermediate Risk Localized Prostate Cancer

BackgroundFocal therapy, including cryotherapy, reduces overtreatment in low- and intermediate-risk prostate cancer (PCa) patients with multiple comorbidities, which seems to increase in popularity compared with whole gland treatment. However, there is currently no consensus regarding the medium-term outcomes of cryosurgery as a prospective alternative to radiotherapy (RT) for such patients. Our study aims to find the available evidence that directly compares the medium-term overall survival (OS) and cancer-specific mortality (CSM) outcomes between cryotherapy and RT in patients with low- and intermediated-risk PCa. Materials and MethodUsing the Surveillance, Epidemiology, and End Results (SEER) database, we identified 47,787 patients with low- and intermediate-risk PCa diagnosed between 2004 and 2015, of which 46,853 (98%) received treatment with RT, while only 934 (2.0%) received treatment with cryotherapy. Kaplan–Meier methods were used to estimateOS and cancer-specific survival (CSS) between the 2 groups. We performed multivariable Cox regression analysis to assess overall mortality (OM), while the cumulative incidence function (CIF) was used to illustrate cancer-specific mortality (CSM) and noncancer-specific mortality (non-CSM) for all patients. Additionally, competing risks regression (Fine-Gray) was implemented to evaluate any differences. After propensity score matching (PSM), all the aforementioned analyses were repeated. After the inverse probability of treatment weighting (IPTW), we repeated Kaplan–Meier methods on OS and CSS, and performed multivariable Cox regression analysis to assess OM in cryotherapy versus RT. Sensitivity analyses were conducted by excluding patients who died of cardiovascular disease. ResultsAfter applying 1:4 PSM to the cryotherapy group with the RT group, the resulting RT cohort consisted of 3,736 patients who were matched with 934 patients in the cryotherapy cohort. The 5‐year OS and cumulative CSM rates for PS-matched groups (N = 4670) receiving cryotherapy (N = 934) or RT (N = 3736) were 89% versus 91.8%, 0.65% versus 0.57, respectively. Multivariable Cox regression analysis demonstrated that cryotherapy was associated with a poorer OS outcome compared to RT (hazard ratio [HR] 1.29, 95% confidence interval [CI]: 1.07-1.55, p < .01). Multivariate competing risk regression analysis revealed that both treatments were not associated with CSS, with HR = 1.07 (95% CI: 0.55-2.08, p = .85). IPTW-adjusted analyses showed that the 5-years OS rates were 89.6% versus 91.8% for cryotherapy versus RT, respectively. Multivariate regression analysis for OS demonstrated that cryotherapy was more likely to have inferior OS in comparison to RT (HR = 1.30; 95%CI: 1.09-1.54; p < .01). The outcome of sensitivity analyses indicates that there was no significant difference in OS and CSS between the 2 groups. ConclusionFor low- and intermediate-risk PCa patients treated by cryotherapy or RT, we could not demonstrate a survival difference. Cryotherapy may be a feasible option as a viable alternative to traditional radiation therapy.

A phase I/IIa study to assess the safety, tolerability, PK, and PD of T3011, a genetically modified oncolytic virus (OVs) administered intravenously (IV) in patients with advanced solid tumors.

2640 Background: T3011 is a genetically modified, next-generation oncolytic HSV-1 with 2 exogenous genes encoding the active heterodimer human IL-12 and the Fab fragment of an anti-human PD-1 antibody. T3011 intratumoral injection (IT) was reported to be well tolerated in patients (pts). IV therapy of OVs is rare and provides an attractive option to many pts with advanced cancers that are not candidates for IT therapy. Methods: It is a phase I/IIa multi-center, open label, single ascending dose (SAD) /multiple ascending dose (MAD) study to evaluate T3011 IV therapy. The primary objective is to evaluate the safety and tolerability. Dose cohort and regimen are shown in Table. PK and PD profiles are tested in samples of blood, saliva, urine, and tumor tissue. Results: As of 16 Dec 2022, 15 pts with stage IV disease were enrolled, 9 pts had received at least 3 lines of prior therapy. The median follow-up time is 1.58 months. Treatment-emergent adverse event (TEAE) occurred in 15 (100%) pts and treatment-related adverse event (TRAE) occurred in 10 (66.7%) pts. G3 TEAE in 3 (20%) pts (hypertriglyceridemia, dyspnea, lymphopenia) and G3 TRAE in 1 (6.7%) pt (lymphopenia), no≥ G4 AE reported. Dyspnea, the only reported SAE (1, 6.7%), is drug-unrelated. TRAEs were lymphopenia (5, 33.3%), anemia (1, 6.7%), diarrhea (1, 6.7%), malaise (1, 6.7%), urticaria (1,6.7%), rash (1, 6.7%), constipation (1, 6.7%), flu like symptoms (1, 6.7%), headache (1, 6.7%) and abnormal laboratory test results (incidence were all 6.7%), most of them are mild and manageable. No AEs led to drug withdrawal. No DLT occurred; MTD was not reached. 11/15 pts achieved stable disease (SD) by RECIST v 1.1. DCR was 73.3%. 1 pt with colorectal cancer who experienced irinotecan-based chemotherapy, anti-VEGF and radiotherapy in Cohort 1 had a long-term SD for over 4 months. In SAD part, T3011 DNA in blood at 2 hours post-dose was detected in 0% (0/3), 0% (0/4), 66.7% (2/3) and 100% (2/2) pts in Cohort 1, 2, 3 and 4 respectively. The DNA copies in pts of Cohort 4 are significantly higher than those of Cohort 3 (Mean viral DNA copies/ul 49.6 vs. 5.7). In cohort 2 of MAD part, T3011 DNA in blood at 2 hours post-dose was detected in 0% (0/3), 66.7% (2/3) and 100% (3/3) pts at C1D1, C1D4 and C1D8 respectively. T3011 DNA was not detected in saliva or urine samples. Pre-existing HSV-1 IgG was shown to hardly affect T3011 activity. Conclusions: T3011 IV is safe and well tolerated, and unlikely to spread to close contacts. Preliminary efficacy is encouraging. T3011 DNA in blood is in a dose-dependent manner with additive effect from repeated doses supporting continued recruitment of pts to higher dose cohorts. Clinical trial information: NCT05598268 . [Table: see text]