Kaplan-Meier Estimates Of Overall Survival Research Articles

Anatomy-guided resections for paralimbic tumors in the temporo-insular region: combining tumor and epilepsy surgery concepts.

Tumors in the temporo-mesial region often extend into the insula and vice versa. The present study investigated the results of a surgical strategy that combines principles of tumor and epilepsy surgery. We retrospectively analyzed 157 consecutive patients with intrinsic brain tumors in the temporo-mesial region, with varying degrees of extensions into the insula (44 patients, 28.0%). The surgical strategy utilized "anatomy-guided resection," targeting specific anatomical compartments infiltrated by the tumor (e.g., temporal pole, anterior temporo-mesial region = uncus and hippocampal head, posterior temporo-mesial, insula) rather than treating the tumor as a single mass. The most frequent histologies were ganglioglioma CNS WHO grade 1 (55 patients, 35.0%) and IDH1 wildtype glioblastoma (36 patients, 22.9%). Tumor infiltration was most commonly found in the anterior temporo-mesial compartment (145 patients, 92.4%). An anterior temporal lobectomy was part of the surgical strategy in 131 cases (83.4%). Seventy-six patients (48.4%) with drug-resistant epilepsy underwent a formal presurgical epilepsy work-up, including depth electrode placement in three cases. Complete resections were achieved in 117 patients (74.5%), with supramarginal resections performed in 89 cases (56.7%). Four patients experienced non-temporary neurological complications (CTCAE grade 3-5). At 6 months, 127 of 147 assessable patients (86.4%) were free from seizures or auras (ILAE class 1), excluding early postoperative seizures (<30 days). At 24 months, 122 of 144 assessable cases (84.7%) remained seizure-free (ILAE class 1). Kaplan-Meier estimates for 5-year overall survival were 98.5% for non-recurrent glioneuronal tumors. The 2-year overall survival estimates were 96.0% for 24 primary diffuse CNS WHO grade 2 and 3 gliomas and 55.2% for 30 patients undergoing first surgeries for glioblastomas/astrocytomas CNS WHO grade 4. Combining both epilepsy and tumor surgery concepts in the surgical treatment of intrinsic brain tumors involving the mesial temporal lobe, often extending into the insula, led to more extensive resections, improved seizure outcomes, and potentially even better patient survival outcomes.

Consensus molecular subtyping of metastatic colorectal cancer expands biomarker-directed therapeutic benefit for patients with CMS1 and CMS2 tumors.

We developed a whole transcriptome sequencing (WTS)-based Consensus Molecular Subtypes (CMS) classifier using FFPE tissue and investigated its prognostic and predictive utility in a large clinico-genomic database of CRC patients (n = 24,939). The classifier was trained against the original CMS datasets using an SVM model and validated in an independent blinded TCGA dataset (88.0% accuracy). Kaplan-Meier estimates of overall survival (OS) and time-on-treatment (TOT) were calculated for each CMS (p < 0.05 considered significant). CMS2 tumors were enriched on left-side of colon and conferred the longest median OS. In RAS-wildtype mCRC, left-sided tumors and CMS2 classification were associated with longer TOT with anti-EGFR antibodies (cetuximab and panitumumab). When restricting to only CMS2, there was no significant difference in TOT between right- versus left-sided tumors. CMS1 tumors were associated with a longer median TOT with pembrolizumab relative to other CMS groups, even when analyzing only microsatellite stable (MSS) tumors. A WTS-based CMS classifier allowed investigation of a large multi-institutional clinico-genomic mCRC cohort, suggesting anti-EGFR therapy benefit for right-sided RAS-WT CMS2 tumors and immune checkpoint inhibitor benefit for MSS CMS1. Routine CMS classification of CRC provides important treatment associations that should be further investigated.

Craniospinal irradiation and/or intraventricular radioimmunotherapy after high-dose chemotherapy and autologous stem cell rescue in patients with CNS retinoblastoma-Safety and outcomes.

The prognosis for patients with central nervous system (CNS) retinoblastoma (RB) (trilateral or stage 4b metastatic RB) treated with high-dose chemotherapy and autologous stem cell transplant (HDC-ASCT) remains poor. The impact of irradiation when administered as part of upfront therapy post HDC-ASCT on treatment outcomes and survival is unknown. We performed a retrospective review of all patients with CNS RB (seven stage 4b, eight trilateral, one pineal lesion belonging to methylation group RB) who underwent induction chemotherapy with an intent to proceed to HDC-ASCT at two institutions. Twelve of 16 patients (n=75%) achieved an objective response to induction chemotherapy, while four patients had progressive/refractory disease; two patients responded to subsequent therapy and proceeded to ASCT, and two patients did not. Seven of 14 patients who underwent HDC-ASCT, received radiotherapy as part of upfront therapy post HDC-ASCT in the form of craniospinal irradiation (CSI) (n=3), intraventricular radioimmunotherapy (n=3), or both CSI and intraventricular radioimmunotherapy (n=1). The Kaplan-Meier estimate of overall survival for these patients was 62.5% at 5years; no patients developed second malignant neoplasms within the radiation fields. For the seven patients who did not receive radiotherapy, the overall survival was 28.6% at 5years. CSI (23.4Gy) alone or in conjunction with intraventricular RIT may have clinical utility in eliminating persistent MRD post HDC-ASCT, contributing to improved disease-free survival in patients with CNS RB. This treatment strategy merits evaluation in a prospective, multicenter clinical trial for patients with CNS metastatic RB.

Partitioned overall survival: Comprehensive analysis of survival states over 4 years in CheckMate 9ER comparing first-line nivolumab plus cabozantinib versus sunitinib in advanced renal cell carcinoma (aRCC).

4507 Background: Immunotherapy regimens can be associated with prolonged disease control after treatment discontinuation without the need for further anticancer therapy. An integrated, comprehensive partitioned survival analysis describes how patients spend overall survival (OS) time, on/off treatment, with/without toxicity. Previous analysis of first-line (1L) nivolumab (NIVO) + ipilimumab (IPI) for aRCC in CheckMate 214 showed treatment-free survival (TFS) twice as long vs sunitinib (SUN). TFS and survival states for immune checkpoint inhibitor plus tyrosine kinase inhibitor (TKI) combination are of interest. Methods: Overall, 651 patients (pts) with aRCC were randomized to receive 1L NIVO + cabozantinib (CABO) or SUN in the CheckMate 9ER trial; treatment continued until progression or intolerance, NIVO for at most 24 months. Minimum follow-up was 4 years. We partitioned area under the Kaplan–Meier (KM) OS curve into 3 survival states, defined from randomization: time on 1L protocol therapy, TFS, and survival after subsequent systemic therapy (second line [2L]) initiation. TFS and protocol therapy were subdivided as mean times with/without reported grade 2+ treatment-related adverse events (TRAEs). Areas under and between KM curves were estimated by 48-month restricted mean times to event. Bootstrapped 95% CIs for between-group differences are reported. Results: At 4 years post randomization, KM estimates of OS were 49.2% vs 40.2% of pts assigned to NIVO+CABO vs SUN, respectively; 17.6% vs 4.7% of pts were surviving treatment-free, and 15.8% vs 8.2% were continuing on 1L protocol therapy. Over the 48-month period since randomization (Table), the mean TFS (95% CI) was 2.4 (0.8–3.9) months longer after treatment with NIVO+CABO than SUN. At least half of TFS was spent with toxicity in both treatment groups, resulting in difference in mean TFS (95% CI) without toxicity of 0.7 (−0.4 to 1.8) month. The NIVO+CABO group spent a mean (95% CI) of 8.5 (6.2–10.8) months more survival time on 1L protocol therapy, whereas the SUN group spent a mean (95% CI) of 6.5 (4.4–8.6) months more survival time after 2L therapy initiation. Conclusions: Over the 4-year period since initiation of 1L therapy for aRCC, the longer OS achieved with NIVO+CABO was accompanied by 1.5 times longer mean time surviving treatment-free before 2L therapy compared with SUN, a smaller difference than seen for NIVO + IPI vs SUN. [Table: see text]

Lenalidomide, rituximab (R2), and ixazomib for frontline treatment of high risk follicular and indolent non-Hodgkin lymphoma

Lenalidomide and rituximab (R2) is an effective frontline treatment for patients with indolent B-cell non-Hodgkin lymphoma (iNHL). We investigated the safety and efficacy of addition of the proteasome inhibitor ixazomib to R 2 for treatment of iNHL through a phase I/II clinical trial for high-risk patients. Twenty patients were enrolled, 18 were treated. The target dose of ixazomib 4 mg weekly was achieved during dose escalation. The most common treatment-related adverse events (AEs) were low grade gastrointestinal, rash, neuropathy, and myalgia/arthralgia. There were 33% grade 2 and 17% grade 3 infections. With median follow-up of 5.2 years, four patients discontinued treatment due to lymphoma progression. Best overall response rate (ORR) was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. Kaplan-Meier estimates of progression free and overall survival (OS) were 73% and 87% at 36 months, respectively. R2 can safely be combined with ixazomib for treatment-naïve iNHL patients.

Intestinal Autotransplantation for Locally Advanced or Locally Recurrent Colon Cancer Invading SMA

Objective: To examine the outcomes of intestinal autotransplantation (IATx) in patients with locally advanced or recurrent colon cancer (LACC or LRCC) invading the superior mesenteric artery (SMA). Background: SMA Involvement in LACC or LRCC is deemed unresectable and is associated with a poor prognosis. Combined extended resections of multiple organs together with SMA, followed by IATx may offer favorable clinical outcomes. However, data on its safety and efficacy are scarce. Design: This retrospective cohort study included patients undergoing IATx between May 2018 and December 2022 in intestinal transplant programs at two university-affiliated hospitals in China. Patients with LACC or LRCC concomitantly with SMA contact of more than 180° were included. Patients with a locoregional peritoneal, pelvic, or distal metastasis were excluded. Results: Ten patients underwent either IATx combined with pancreaticoduodenectomy (n=8) or IATx alone (n=2). Eight patients (80%) were male, and the median age was 55 years (range, 32 – 71 y). The Kaplan-Meier estimates for recurrence-free survival and overall survival at 3 years after IATx were 68% and 80%, respectively. No perioperative deaths occurred. All ten patients experienced postoperative complications including Clavien-Dindo grade I (n=1), grade II (n=4), grade IIIa (n=1), grade IIIb (n=3) and grade IVa (n=1), which comprised acute venous thromboses, upper gastrointestinal hemorrhage, anastomotic leak, gastropareses and significant pleural effusions. With an average follow-up of 23.9 months, eight patients (80%) were currently alive without evidence of disease. Conclusion: Extended resection for LACC or LRCC invading SMA can be performed safely and is associated with prolonged survival.

Global Proteomics Identifies CDK11A/B As Integral to Myeloma Proliferation and High-Risk Disease

Category Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational Introduction Although there have been many treatment advances for multiple myeloma (MM) that have led to increases in overall survival (OS) and progression free survival (PFS) for up to 20 years, the subset of patients with high-risk disease continue to have poor clinical outcomes, with median OS of less than 3 years. Our studies have focused on improving gene expression profiling (GEP) and IMWG risk classification of newly diagnosed MM (NDMM) by proteomics. We have developed a 60-protein risk score (PEP60) that captures a group of high-risk NDMM cases misclassified as low-risk by GEP70, a powerful 70-gene mRNA risk score. We discovered that protein and mRNA have low heterogeneity in MM (R=0.37). Strikingly, CDK11A/B was ranked top 14 th for inferior survival (OS) at the protein level but did not make it into the top 1000 most significant genes at the mRNA level, which was supported by low correlation (R=0.25). CDK11A/B has been previously identified as a druggable target in MM (Tiedemann et al. Cancer Res. 2012; 72(3): 757-768) and our study is the first to confirm its significance at the protein level in a large global proteomics study of patient samples (n = 167). Altogether, this study highlights the importance of discovering high-risk targets at the protein level and identifies CDK11A/B as a high-risk protein that would have been missed in transcript-only analysis. Materials and Methods Total protein from primary bone marrow samples of CD138+ purified plasma cells was subjected to mass spectrometric analysis (n = 167 NDMM). A chromatogram library was assembled with Data Independent acquisition (DIA) spectra and precursor spectra were acquired after each DIA duty cycle, as previously described (Searle et al. Nat Commun 2018, 9:5128). Following data acquisition, data were searched using an empirically corrected library and a quantitative analysis was performed to obtain a comprehensive proteomic profile. Proteins were identified and quantified using EncyclopeDIA and visualized with Scaffold DIA using 1% false discovery thresholds at both the protein and peptide level. Expression was normalized by Variance Stabilizing Normalization (VSN). Heterogeneity between protein and mRNA (microarray) expression were compared across genes using Pearson correlation. Using the maxstat package in R, log-rank tests on 4,760 proteins were conducted and 60 high-risk proteins were selected (FDR&amp;lt;0.1%) to develop a prognostic protein risk score (PEP60). Kaplan-Meier curves revealing overall survival (OS) were constructed using the survival package in R. Results: A geometric mean ratio of 34 upregulated proteins divided by 26 downregulated proteins (PEP60), sorted from low to high, show that patient deaths increase in Heatmap with increase in PEP60 score. Kaplan-Meier estimates of OS PEP60 and OS GEP70 in low-risk myeloma and high-risk myeloma showed increased inferior survival for PEP60 OS (P&amp;lt;0.001; HR = 4.49) compared to GEP70 OS (P&amp;lt;0.001; HR = 3.64). Kaplan-Meier estimates of OS for PEP60high/GEP70high (black), PEP60high/GEP70low (red), PEP60low/GEP70high (brown), and PEP60low/GEP70low (blue) showed significant inferior survival for the PEP60high/GEP70high group (P&amp;lt;0.001, HR = 9.07) compared to PEP60high/GEP70low (P&amp;lt;0.001, HR = 3.70) and PEP60low/GEP70high (P&amp;lt;0.001, HR = 3.03), demonstrating that PEP60 and GEP70 capture separate high-risk patients when only one is high ( Fig 1). Correlation of CDK11A/B mRNA (microarray) and protein show low correlation (R=0.25).Kaplan-Meier estimates of OS for CDK11A/B were highly significant for protein (P&amp;lt;0.001; HR = 3.00) ( Fig 2) but not as significant for mRNA (P=0.02; HR = 1.86). Conclusion Protein and mRNA correlation of paired samples from 167 NDMM patients reveals a wide heterogeneity between expression at the mRNA and protein levels. Global proteomics Identified a subset of patients that have inferior survival that were previously missed in our high-risk model using mRNA expression (GEP70). CDK11A/B was identified as highly significant for inferior survival (OS) at the protein level but not at the mRNA level. This study shows the importance of proteomics for capturing high-risk proteins and identifies CDK11 A/B as a high-risk, druggable target in patients samples.

Blast Clearance after High Dose-Melphalan Conditioning for Allogeneic Stem Cell Transplantation in Relapsed and Refractory Acute Myeloid Leukemia

Introduction: For patients (pts) with relapsed or refractory acute myeloid leukemia (r/r AML) allogeneic stem cell transplantation (ASCT) has become an established highly effective and potential curative treatment option. Even for pts with active disease, direct ASCT using sequential conditioning regimens has shown promising outcomes. In this retrospective study, we examined prognostic factors for long-term survival in r/r AML pts with active disease with special focus to the prognostic value of blast clearance during condition therapy. Patients and Methods: 186 r/r AML pts treated with sequential conditioning regimens at our center between 2014-2023 were included in our analysis. Patients underwent high-dose melphalan (100 - 140 mg/m 2, day -11 prior ASCT) followed by either fractionated total body irradiation with 8 Gy (TBI, n = 71) or non-TBI regimens (busulfan, n = 101, or treosulfan, n = 14) in combination with fludarabin (120 - 150 mg/m 2) from day -6 before ASCT. TBI-based conditioning was applied almost exclusively in patients aged &amp;lt; 60 years. Graft versus host-disease (GvHD) prophylaxis consisted of calcineurin inhibitors, mycophenolate and anti-T-lymphocyte globulin. In 180 out of 186 patients, blast clearance was assessed by cytologic and flow cytometric blast count via bone marrow (BM) aspirate in median 5 days after Melphalan and prior to continuation of the sequential conditioning therapy. Blast clearance was defined as cytologic BM blast count &amp;lt; 5% and &amp;lt; 0.1% BM cells with leukemia-associated immunophenotype in flow cytometry. Results: Median pts age was 67 years (range 45 - 76 years) in the non-TBI group and 51 years (range 19 - 71 years) in the TBI group, respectively. Median follow up of surviving patients was 46 months. As expected, comorbidities and disease-specific factors varied between these groups. HCTCI scores &amp;gt; 3 points were observed in 14% of TBI pts compared to 32% in non-TBI pts ( p .01) and 45% versus 54% harbored adverse risk genetics according to European Leukemia Net (ELN) 2017 classification ( p .41), respectively. In the non-TBI group, 38% of the pts had a secondary or therapy-related AML compared to 20% of pts in the TBI group ( p .03). HLA-mismatched (&amp;lt;10/10 matched) donor grafts were transplanted in 21% (TBI) vs. 20% (non-TBI) of the pts. 185 of 188 pts received GCS-F mobilized stem cell grafts; 3 pts received a bone marrow graft. Kaplan-Meier estimates for overall survival (OS) with and without blast clearance at 2 years were 69.6% (95% CI 60.1-80.6%) vs. 58% (95% CI 48.8-69.1%, p .33), for event free survival (EFS, event defined as death or overt relapse) 58.9% (95% CI 49-70.8%) vs. 46.1% (95% CI 36.7-58.1%, p .2), respectively. We included the re-occurrence / persistence of defined molecular and cytogenetic markers or decreasing CD34 + bone marrow chimerism (&amp;lt; 95%) after transplant as measures for impending relapse as a modified EFS. The EFS including impending relapse was 49.8% (95% CI 40-62%) vs. 36.4% (27.7-47.8%) after 2 years. A non-significant trend with reduced relapse risk for those patients who achieved blast clearance after Melphalan ( p .1, HR 0.73) was observed. Most patients with impending relapse showed similar survival as patients without evidence of relapse after ASCT. In multivariate cox regression, age, HCTCI scores &amp;gt; 3 points, adverse risk according to ELN 2017 definitions and donor mismatch &amp;lt; 10/10 resulted in adverse prognosis. Especially, patients with mismatched donors displayed highly significant inferior outcomes. Both leukemic burden prior to ASCT as well as blast clearance after melphalan showed no significant correlation with clinical outcome parameters. Conclusion: Sequential conditioning regimens followed by ASCT offer long-term survival for more than 50% of pts with active relapsed or refractory AML. Patients who did not achieve complete blast clearance during conditioning therapy showed a trend towards higher relapse risk after ASCT which did not result in inferior survival. This underscores the importance of close monitoring and early interventions such as accelerated immunosuppression tapering, preemptive donor lymphocyte infusions and targeted therapies in case of impending relapse after ASCT.

Treosulfan-Based Conditioning Prior to Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) for Patients with Myelodysplastic Syndrome (MDS): Comparative Analysis of a Randomized Controlled Trial and Real-World Data

Introduction MDS is a clonal myeloid disorder manifested by diverse genotypes and phenotypes, characterized by ineffective hematopoiesis. AlloHSCT is the only potential curative therapy for MDS. Myeloablative conditioning regimens are integral part of alloHSCT that allow engraftment and provide a therapeutic effect. Treosulfan has myeloablative and immunosuppressive properties and provides less transplantation related mortality than some of the traditionally used myeloablative conditioning regimens like busulfan-based treatments. In our analysis, we compared the results from the MDS subgroup of the randomized controlled trial (RCT) MC-FludT.14/L (NCT00822393) with real-world data (RWD) of patients treated at the University Hospital Münster and the University Hospital Dresden. Methods MDS patients conditioned with treosulfan (30 g/m²) and fludarabine in the RCT (June 2013 to January 2018) and the data obtained from 2 hospitals (RWD) (August 2017 to February 2023) were compared. Baseline characteristics, overall survival, relapse-free survival, relapse (or progression), non-relapse mortality, time to engraftment, and safety profiles between the RCT and RWD were compared. A sensitivity analysis was conducted using propensity score matching (PSM). Additionally, subgroup analyses evaluated the clinical effectiveness of treosulfan by baseline morphologic blast count and the revised International Prognostic Scoring System (IPSS-R). Results Overall, 195 MDS patients (RCT 84, RWD 111) with at least 12 months follow-up were analyzed. Median age was 62 years (range 39-76 years). Baseline characteristics only differed between the RCT and RWD with respect to age, IPSS-R categories, Hematopoietic Cell Transplantation Co-Morbidity Index total score (HCT-CI), and neutrophil count, indicating some heterogeneity between the RCT and RWD patients. In the PSM analysis, 106 (RCT 53, RWD 53) patients were matched to address the heterogeneity. The Kaplan-Meier estimates for overall survival (OS) at 2 years were 73% (95% CI 62-81%) and 72% (95% CI 62-81%) for the RCT and RWD (Figure 1), and for relapse-free survival (RFS) at 2 years were 68% (95% CI 57-77%) and 67% (95% CI 56-76%), respectively. Cumulative incidence of relapse at 2 years was 11% (95% CI 4-18%) and 15% (95% CI 7-23%), and for non-relapse mortality (NRM) was 21% (95% CI 12-30%) and 18% (95% CI 10-26%) for the RCT and RWD, respectively. In addition, cumulative incidence of neutrophil engraftment at 28 days was 93% (95% CI 87-98%) and 94% (95% CI 89-98%) for the RCT and RWD, while the median engraftment time was later in the RCT (19 days vs 15 days). Cumulative incidence of platelet engraftment at 28 days was 89% (95% CI 83-96%) and 93% (95% CI 88-98%) for the RCT and RWD, with the same median time 14 days. Further, the PSM sensitivity analysis showed comparable efficacy between the RCT and RWD. Interestingly, bone marrow blast count prior to conditioning and IPSS-R subgroups only had minor, statistically not significant impact on survival endpoints (Table 1). The number of deaths were 27 (32%) and 28 (25%) in the RCT and RWD, respectively. The most frequent cause of death was transplantation related (20% vs 14%). One patient experienced primary graft failure in the RCT and none in the RWD. More patients had acute GVHD with at least grade 2 in the RCT (27%) than in RWD (18%). Conclusions The efficacy and safety of treosulfan-based conditioning therapy prior to alloHSCT in post-authorization real world setting was comparable with the results obtained from the RCT. Our data suggest that bone marrow blast count is no strong predictor for survival after alloHSCT. Therefore, we conclude that the approved treosulfan-based conditioning therapy for patients with MDS, including those with increased blasts, has promising outcomes after alloHSCT.

Applying the Novel EHA/EBMT Grading System for Icaht Following CAR-T Therapy: Comparative Incidence across Disease Entities and Association with Infections and Mortality

Background: Hematological toxicity is a frequent side effect of CAR-T therapy and predisposes for severe infectious complications. Recently, the EHA/EBMT consensus grading for Immune Effector Cell Associated HematoToxicity (ICAHT) was developed ( Rejeski et al. Blood 2023). In contrast to existing grading systems such as the CTCAE, the novel ICAHT grading integrates both the depth and duration of neutropenia. We hypothesized that ICAHT severity is associated with key clinical sequelae such as transfusion requirements, hospitalization, severe infections, and adverse treatment outcomes. Methods: We applied the novel grading of early ICAHT (day 0-30) to a multicenter retrospective real-world cohort of 549 patients treated with BCMA- or CD19-directed CAR T-cells for relapsed/refractory B-cell malignancies (334 large B-cell lymphoma [LBCL], 112 multiple myeloma [MM], 103 mantle cell lymphoma [MCL]) across twelve international sites (Germany, France, Spain, USA). Hematotoxicity endpoints included the total cumulative duration of severe neutropenia (ANC &amp;lt;500/µL, day 0-60) and phenotypes of neutrophil recovery ( Rejeski et al. Blood 2021). Infections were studied until day +90 after CAR-T and were graded on a 5-grade scale as mild, moderate, severe, life-threatening, or fatal. Non-relapse mortality (NRM) was defined as death following CAR-T without evidence of relapse or progression. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) were compared using log-rank test. Results: Our study cohort included 424 patients without severe ICAHT (absent or grade 1-2) and 125 patients with severe ICAHT (grade 3-4). The distribution of mild (1°), moderate (2°), severe (3°) and life-threatening (4°) ICAHT was 36%, 29%, 17%, and 5%. Seventy patients (13%) did not develop ICAHT of any grade. When comparing ICAHT grades across disease entities, we noted a numeric trend towards increased severe ICAHT in MCL compared to LBCL or MM patients (Grade ≥3: 28% vs. 23% vs. 15%). Patients that subsequently developed severe ICAHT displayed elevated serum inflammatory markers and pronounced cytopenia at baseline - reflected by increased CAR-HEMATOTOX scores (median 3 vs. 1, p&amp;lt;0.0001). On multivariate binary logistic regression, co-stimulatory domain (CD28z), low platelet count, low ANC, low hemoglobin, increased serum ferritin, and the presence of bone marrow infiltration were independent risk factors for severe ICAHT. We noted a strong positive correlation between ICAHT severity and the cumulative duration of severe neutropenia (r=0.92, p&amp;lt;0.0001). The aplastic phenotype of neutrophil recovery was enriched in patients with grade 3 (73%) and especially grade 4 ICAHT (100%). Severe ICAHT was also associated with coincident multilineage cytopenias, resulting in increased transfusion requirements for both platelets (85% vs. 21%, p&amp;lt;0.0001) and red blood cells (86% vs. 41%, p&amp;lt;0.0001). In terms of management of hematotoxicity, the severe ICAHT group more commonly received G-CSF (72% vs. 44%, p=0.01), TPO mimetics (12% vs. 2%, p&amp;lt;0.0001) and hematopoietic stem cell boosts (6% vs. 0.2%, p&amp;lt;0.0001). Importantly, patients with severe ICAHT displayed a significantly increased rate of severe infections (49% vs. 13%, p&amp;lt;0.0001, Fig. 1a) and severe bacterial infections (36% vs. 8%, p&amp;lt;0.0001). This translated into a markedly increased 1-year NRM rate (14% vs. 4.5%, logrank p&amp;lt;0.0001, Fig. 1b), which was primarily attributed to fatal infections of fungal or bacterial origin. Of note, the ICAHT grading showed superior discrimination for severe infections (C-index 0.73, 95%CI: 0.67-0.78) compared to CTCAE grading (C-index 0.55, n.s.). Prolonged hospitalization was noted in case of severe ICAHT (median 21 vs. 16 days, p&amp;lt;0.0001) and intensive care admission was more common (23% vs. 4%, p&amp;lt;0.001). Finally, we observed inferior PFS (1-year PFS 35% vs. 51%, median 4 vs. 14 months, p&amp;lt;0.0001) and inferior OS (1-year OS 52% vs. 73%, median 12 months vs. not-reached, p&amp;lt;0.0001) in the patients that developed severe ICAHT. Conclusions: These data highlight the clinical relevance of the novel EHA/EBMT ICAHT grading system. Importantly, ICAHT severity was closely associated with transfusion dependence, increased infection incidence, and adverse treatment outcomes with high NRM. Taken together, these findings argue for reporting ICAHT grades in clinical trials evaluating established and novel CAR constructs.

Real-world treatment patterns and survival outcomes for patients with stage III non-small cell lung cancer in Spain: a nationwide cohort study.

The burden of non-small cell lung cancer (NSCLC) remains high in Spain, with lung cancer accounting for 20% of cancer-related deaths annually. Programs such as the Spanish Thoracic Tumour Registry (TTR) and the global I-O Optimise initiative have been developed to observe patients in clinical practice with the aim of improving outcomes. This analysis examined treatment patterns and survival in patients with stage III NSCLC from the TTR. These patients represent a heterogenous group with complex treatment pathways. The TTR is an ongoing, observational, prospective, and retrospective cohort multicentre study (NCT02941458) that follows patients with thoracic cancer in Spain. Adults aged ≥18 years with stage IIIA/IIIB NSCLC enrolled in the TTR between 01 Jan 2010 and 31 Oct 2019 were included in this analysis. Initial treatment received was described by cancer stage and histology (squamous and non-squamous NSCLC). Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) were calculated over a 5-year period. A total of 1,838 patients were included in the cohort, including 1,082 with stage IIIA (58.9%) and 756 with stage IIIB (41.1%). Median follow-up was 18.3 months. The median age of patients was 66 years, and most had non-squamous NSCLC (54.0%), were male (81.2%), and were active or former smokers (93.4%). Overall, 26.3% of patients received surgical resection (37.0% for stage IIIA and 11.1% for stage IIIB). The most frequent initial treatment received was concurrent chemoradiotherapy for stage IIIA (30.2%) and stage IIIB (37.0%) patients. Median OS was lower in patients with stage IIIB than stage IIIA (28 vs. 37 months) disease and was lower for patients with squamous than non-squamous histology (19 vs. 26 months). Median PFS and OS varied when patients were stratified by initial treatment. This TTR analysis describes the clinical reality surrounding the initial management and survival outcomes for stage III NSCLC in Spain and presents survival outcomes comparable with other real-world evidence. It provides insights into the diverse approaches used before the availability of immunotherapies and targeted treatments in the non-metastatic NSCLC setting.

Local Control after Re-Irradiation of Spinal Metastases with Stereotactic Body Radiation Therapy

Determine local control (LC) rate and risk of vertebral compression fractures (VCFs) and radiation myelitis (RM) for patients receiving re-irradiation of spinal metastases (SMs) using stereotactic body radiation therapy (SBRT) from large single-institutional experience with long follow-up. Retrospectively identified patients receiving re-irradiation SBRT (rSBRT, 1, 3, or 5 fractions) to SMs previously treated with radiation therapy (RT) and having follow up imaging to assess local control. 1 fraction patients typically received 20-24 Gy and 16-18 Gy to the high- and low-risk planning target volumes (PTVs), respectively, and 27-39 Gy and 21-24 Gy for the 3 fraction patients, with a single level of 50 Gy for 5 fractions. Patient and treatment characteristics for previous RT (pRT) and rSBRT were collected, including histology and dose-volume histogram statistics (DVH). Kaplan-Meier estimates of overall survival (OS), and cumulative incidence (competing with death) of local failure with death as a competing risk was computed for the whole cohort and stratified by radioresistance of histology, and risk of VCF for RM (for treatments at L1 and above) and 95% confidence intervals. Equivalent dose in 2 Gy fractions (EQD2) for PTV and spinal cord (SC) DVH statistics was computed for each individual course and cumulatively, using a/b = 10 Gy for tumor and 2 Gy for SC. Identified 107 lesions in 91 patients. 48 (45%) had radioresistant histologies. For all patients, at 1 and 2 years, respectively OS was 64% (55-74%) and 43% (34-55%), LC was 88% (81-94%) and 85% (78-91%) with median follow-up of 52 months (Table 1). OS and LC were not significantly different between radiosensitivity groups (p>0.05). Risk of VCF at 1 and 2 years was 7% (3-13%) and 9% (4-16%). RM was identified in 1 patient, who received 30 Gy in 5 fractions to T1, and had 1-fraction rSBRT 21 months later. SC Dmax was 31.5 Gy for pRT and 10.4 Gy, for rSBRT, resulting in total SC EQD2 of 73 Gy. RM was confirmed on MRI 8 months after rSBRT. Cumulative RM risk at 8 months after rSBRT was estimated at 1% (0-4%). Median EQD2 for the minimum dose to the high and low risk PTVs were 17.7 Gy (interquartile range, IQR, 13.0-27.6 Gy) and 13.7 Gy (IQR, 10.8-19.3 Gy) for rSBRT, and maximum EQD to SC for previous RT, rSBRT, and cumulatively was 38 Gy (IQR, 30-41 Gy), 27 Gy (IQR, 22-36 Gy), and 65 Gy (IQR, 54-73 Gy).Re-irradiation of spinal metastasis with SBRT can be delivered safely and provide high rates of local control, including for radioresistant tumors, as demonstrated with the longest reported follow-up in this setting. Re-irradiation of SM with SBRT provides high rates of LC even for radioresistant tumors, and low risk of VCF and RM, based on the longest reported follow-up in this setting.

Characteristics and Outcomes of De Novo Genitourinary Malignancy in Solid Organ Transplant Recipients at the University of Minnesota

Studies examining outcomes of genitourinary malignancy (GU) in the solid organ transplant (SOT) population predominantly focus on renal transplant recipients and consist of relatively small cohorts. We aimed to expand knowledge of the characteristics and outcomes of de novo GU malignancies in all patients with SOT at a large tertiary center. The SOT database was queried for recipients with de novo bladder, renal cell, and prostate malignancy, and a retrospective chart review was performed. Descriptive statistics and Kaplan-Meier survival estimates were calculated. Cox proportional hazards regression was used for multivariate modeling of predictive factors in the development of GU malignancy. Solid organ transplant recipients with de novo bladder malignancy comprised 64.3% with high grade and 38.1% with advanced stage (≥T2) disease at initial diagnosis. Only 3.7% of patients with de novo renal cell carcinoma presented with metastatic disease, and 13.6% with localized disease developed recurrences. The most common stage in de novo prostate cancer patients was pT3 (52.2%). Kaplan-Meier estimates (95% CI) for 5-year overall (OS) and cancer-specific survival (CSS) were 44.12% (31.13-62.52) and 80.80% (68.85-94.81) for bladder, 78.90% (68.93-90.30) and 96.61% (92.10-100.00) for renal cell, and 81.18% (72.01-91.51) and 96.16% (90.95-100.00) for prostate cancer, respectively. Age at transplant and time from transplant to cancer diagnosis were predictive of de novo bladder cancer OS (P=.042 and .021, respectively). To our knowledge, this is the largest single-center cohort examined for GU malignancy after SOT. Bladder and renal cell cancer had worse OS but similar CSS as historical rates for nontransplant patients. De novo prostate cancer had similar CSS.

Contemporary outcomes of patients undergoing robotic-assisted radical cystectomy: A comparative analysis between intracorporeal ileal conduit and neobladder urinary diversions

ObjectiveWe aimed to compare perioperative and oncologic outcomes for patients undergoing robotic-assisted radical cystectomy (RARC) with intracorporeal ileal conduit (IC) and neobladder (NB) urinary diversion. MethodsPatients undergoing RARC with intracorporeal urinary diversion between January 2017 and January 2022 at the Icahn School of Medicine at Mount Sinai, New York, NY, USA were indexed. Baseline demographics, clinical characteristics, perioperative, and oncologic outcomes were analyzed. Survival was estimated with Kaplan-Meier plots. ResultsOf 261 patients (206 [78.9%] male), 190 (72.8%) received IC while 71 (27.2%) received NB diversion. Median age was greater in the IC group (71 [interquartile range, IQR 65–78] years vs. 64 [IQR 59–67] years, p<0.001) and BMI was 26.6 (IQR 23.2–30.4) kg/m2. IC group was more likely to have prior abdominal or pelvic radiation (15.8% vs. 2.8%, p=0.014). American Association of Anesthesiologists scores were comparable between groups. The IC group had a higher proportion of patients with pathological tumor stage 2 (pT2) tumors (34 [17.9%] vs. 10 [14.1%], p=0.008) and pathological node stages pN2–N3 (28 [14.7%] vs. 3 [4.2%], p<0.001). The IC group had less median operative time (272 [IQR 246–306] min vs. 341 [IQR 303–378] min, p<0.001) and estimated blood loss (250 [150–500] mL vs. 325 [200–575] mL, p=0.002). Thirty- and 90-day complication rates were 44.4% and 50.2%, respectively, and comparable between groups. Clavien-Dindo grades 3–5 complications occurred in 27 (10.3%) and 34 (13.0%) patients within 30 and 90 days, respectively, with comparable rates between groups. Median follow-up was 324 (IQR 167–552) days, and comparable between groups. Kaplan-Meier estimate for overall survival at 24 months was 89% for the IC cohort and 93% for the NB cohort (hazard ratio 1.23, 95% confidence interval 1.05–2.42, p=0.02). Kaplan-Meier estimate for recurrence-free survival at 24 months was 74% for IC and 87% for NB (hazard ratio 1.81, 95% confidence interval 0.82–4.04, p=0.10). ConclusionPatients undergoing intracorporeal IC urinary diversion had higher postoperative cancer stage, increased nodal involvement, similar complications outcomes, decreased overall survival, and similar recurrence-free survival compared to patients undergoing RARC with intracorporeal NB urinary diversion.

Disease-Free Survival Does Not Differ According to Fertility Preservation Technique for Young Women With Breast Cancer

ABSTRACT Approximately 5% of breast cancer cases occur in women younger than 40 years, and the 5-year overall survival for women between the ages of 15 and 44 years is 90%. As the childbearing age increases, so too does the proportion of women who wish to achieve pregnancy after breast cancer. The conception rate among these women is 40% lower than the general population, as a result of advanced age and the gonadal toxicity of chemotherapy. Fertility preservation (FP) techniques enable young patients to freeze gametes before treatment; however, the most recommended method of FP is oocyte or embryo vitrification after controlled ovarian hyperstimulation (COH), which has limited safety data in breast cancer patients. This retrospective cohort study aimed to evaluate disease-free survival (DFS) in a large cohort of women with breast cancer who underwent FP techniques with or without COH. Patients with breast cancer between 18 and 43 years old referred for FP to 2 university hospitals between July 2013 and July 2019 were included. Women not included in the FP program after oncofertility counseling, those with stage 4 disease at diagnosis or history of other invasive cancer, or those with gonadotoxic treatment have been excluded. Patients were split into 2 groups, with the STIM group receiving at least 1 COH protocol using a gonadotropin-releasing hormone antagonist with or without an aromatase inhibitor and the no STIM group not undergoing ovarian stimulation. Patient characteristics, obstetric variables, and oncology characteristics were collected from medical records. Disease-free survival and overall survival were estimated using Kaplan-Meier plots and compared between the 2 groups by log-rank test. A total of 740 women (76.7%) who attended oncofertility consultations for breast cancer were included. Of these, 328 (44.3%) underwent at least 1 ovarian stimulation cycle, and 412 (55.7%) had an FP technique without exogenous FSH administration. The STIM group was significantly older and had lower values in ovarian reserve tests, and more women in the no STIM group underwent a mastectomy and neoadjuvant chemotherapy. The proportion of patients with hormone receptor-positive tumors was equal in both groups. Letrozole was coadministered with exogenous gonadotropin in 39.3% of women in the STIM group (Let-COH). Overall, 16.8% of patients had a tumor still present on oocyte retrieval after COH, of which 55% received a Let-COH protocol. Follow-up data were available for 80.9% (559/740) of patients. Cancer recurrence was documented in 87 patients (27 in STIM, 60 in no STIM), and DFS was not statistically different between the groups (log-rank test P = 0.09). Neither difference in DFS nor overall survival was observed in the Let-COH group compared with those undergoing COH after breast surgery. Kaplan-Meier estimates of overall survival at 4 years were 97.6% in the STIM and 93.6% in the no STIM groups, and after adjusting for prognostic parameters, the risk of death remained significantly lower in the STIM group (hazards ratio, 0.55 [0.35–0.85]). The results of this large retrospective cohort study demonstrate that the use of COH for FP patients with breast cancer before or after breast tumor surgery is safe; however, a longer duration of follow-up will provide a more definite safety profile.

Long-term outcome for patients with advanced non‒small-cell lung cancer treated by autologous cytokine-induced killer (CIK) cell immunotherapy in combination with sintilimab plus chemotherapy: NSCLC-CCICC-002.

9096 Background: Autologous cytokine-induced killer (CIK) cell immunotherapy in combination with Sintilimab demonstrated robust antitumor activity and safety in the phase Ib CCICC-002 study (NCT03987867) of Non‒Small-Cell Lung Cancer. Long-term outcomes in patients are reported herein. Methods: Systemic therapy naïve patients received platinum-based doublet chemotherapy, Sintilimab (PD1 inhibiter), and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or two years. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. OS and PFS were based on immune-related response criteria by investigator assessment (data cut-off, January 31, 2023). Results: From May 2019 to Jan 2021, CCICC-002 enrolled 33 patients（19 squamous, 14 non-squamous NCSLC; 1 patient was excluded because the second biopsy revealed EGFR mutation) aged 46-73 years with median follow-up was 31.4 months (range, 7.6-44.4 months). Estimated 3-year OS was 51.8% in all patients; median OS was not reached (95% CI, 26.6 months-not reached) in all patients. In subgroups, median OS was 27.6 months (95% CI, 13.4 months-not reached) in squamous NCSLC and not reached (95% CI, 29.9 months-not reached) in non-squamous NCSLC, respectively. Median OS was not reached (95% CI, 27.6 months-not reached) in PD-L1 positive patients and 28.3 months (95% CI, 15.6 months-not reached) in PD-L1 negative patients, respectively. Estimated 3-year PFS rate was 27.5% and median PFS was 17.9 months (95% CI, 8.2-26.5 months) in all patients. Median PFS was 17.3 months (95% CI, 5.0-24.0 months) in squamous NCSLC and 22.4 months (95% CI, 5.7 months-not reached) in non-squamous NCSLC, respectively. Median response duration was 18.7 months (95% CI, 10.1-27.6 months). 30.3% of patients were ongoing at data cut-off, and the longest response was ongoing at 41.3 months. 1 of the 5 CMR (complete metabolic response by PET-CT) patients experienced disease progression during observation. Treatment-related AEs (TRAEs) occurred in 94.0% of patients and resulted in study discontinuation in 7.8%, and 15.2% experienced grade 3/4 TRAE. Conclusions: This long-term analysis of CCICC-002 represents the longest follow-up for CIK to date and confirms the durable antitumor activity and tolerability of CIK cells therapy in combination with Sintilimab plus chemotherapy in advanced NCSLC. Further studies are warranted to confirm these preliminary results. Clinical trial information: NCT03987867 .

Introduction of E-Score: A gene expression score to characterize immunogenic versus oncogenic HPV expression in HNSCC.

6057 Background: Human Papillomavirus (HPV) integration in the human genome occurs in a majority of HPV(+) head and neck squamous cell carcinomas (HNSCC), with direct and indirect effects on host gene expression and tumorigenesis. Although previous studies showed that HPV integration in HNSCC is overrepresented in genes often somatically mutated in head and neck, lung, and urogenital cancers, reports are mixed for whether patients with HPV integration have worse clinical outcomes. These disparate results may be due to differences in how integration is defined. Integration can often lead to partial loss of the viral genome (e.g. HPV genes E1, E2, or E5) with retention of the oncogenes E6 and E7, which led to a low E2/E7 expression ratio being used as a biomarker for integration. Conversely, others have used the direct detection of DNA or RNA HPV-human breakpoints to identify tumors harboring integrated HPV. HPV integration and the retention or deletion of HPV genes can dramatically change the expression of HPV genes, and we hypothesize it also affects the host immune response. Hypothesis: Loss of non-oncogenic HPV genes relative to E6 and E7 levels reduces immunogenicity, leading to weakened immune cell infiltration and worse clinical outcomes. Methods: Bulk RNA sequencing data from HPV(+) HNSCC tumors (n = 136) was used to characterize the differences in retention or loss of HPV genes and calculate the E-Score as the sum of the logCPM of HPV genes E1, E2, E4, and E5 relative to E7. Cell type deconvolution was performed using ComBat to correct for batch effects, and CIBERSORTx to quantify cell type proportions within the tumor samples. Kaplan-Meier estimates of recurrence and overall survival (OS) were calculated, and Cox proportional hazards tests with covariates were used to test for association with recurrence and OS. To test the correlation between immune cell type inferred proportions and E-Score, T-Tests were performed between samples with high and low E-scores. Results: Low E-Score was significantly associated with recurrence (p = 0.012) but not with OS (p = 0.39) in the multivariate model accounting for age, tumor stage (AJCC8), smoking status, drinking status, BMI, marital status, and molecular tumor subtype (defined as IMU or KRT). For integration positive samples (n = 66), higher E-Score, suggesting lower rates of HPV gene loss, was correlated with higher percentages of dendritic cells (p = 0.044), macrophages (p = 0.021), and CD8+ T Cells (p = 0.024), but not CD4+ T cells (p = 0.14). This significance did not hold when looking at integration negative samples. Conclusions: These results suggest that HPV+ HNSCC patients with a loss of E1, E2, E4 and E5 tend to have less immune cell infiltration and are more likely to have recurrence. We conclude that E-Score is a potential prognostic biomarker of recurrence in HPV+ HNSCC and potential predictive biomarker for immunotherapy.

The HI-FIVE Trial: A Prospective Trial Using 4-Dimensional 68Ga Ventilation-Perfusion Positron Emission Tomography-Computed Tomography for Functional Lung Avoidance in Locally Advanced Non-small Cell Lung Cancer

Functional lung avoidance (FLA) radiation therapy aims to spare regions of functional lung to reduce toxicity. We report the results of the first prospective trial of FLA using 4-dimensional gallium 68 ventilation-perfusion positron emission tomography-computed tomography (68Ga-4D-V/Q PET/CT). Inclusion criteria required a diagnosis of stage III non-small cell lung cancer and the ability to undergo radical-intent chemoradiation therapy. Functional volumes were generated using planning 68Ga-4D-V/Q PET/CT. These volumes were used to generate a clinical FLA plan to 60 Gy in 30 fractions. The primary tumor was boosted to 69 Gy. A comparison anatomic plan was generated for each patient. Feasibility was met if FLA plans (compared with anatomic plans) allowed (1) a reduction in functional mean lung dose of ≥2% and a reduction in the functional lung volume receiving 20 Gy (fV20Gy) of ≥4%, and (2) a mean heart dose ≤30 Gy and relative heart volume receiving 50 Gy of <25%. In total, 19 patients were recruited; 1 withdrew consent. Eighteen patients underwent chemoradiation with FLA. Of the 18 patients, 15 met criteria for feasibility. All patients completed the entire course of chemoradiation therapy. Using FLA resulted in an average reduction of the functional mean lung dose of 12.4% (SD, ±12.8%) and a mean relative reduction of the fV20Gy of 22.9% (SD, ±11.9%). At 12 months, Kaplan-Meier estimates for overall survival were 83% (95% CI, 56%-94%) and estimates for progression-free survival were 50% (95% CI, 26%-70%). Quality-of-life scores were stable across all time points. Using 68Ga-4D-V/Q PET/CT to image and avoid functional lung is feasible.

Laparoscopic or Open Adrenalectomy for Stage I-II Adrenocortical Carcinoma: A Retrospective Study.

Surgical resection of adrenocortical carcinoma (ACC) is the only curative treatment. Even in localized (I-II) stages, open adrenalectomy (OA) is the gold standard, though laparoscopic adrenalectomy (LA) can be proposed in selected patients. Despite the postoperative benefits of LA, its role in the surgical management of patients with ACC remains controversial regarding oncologic outcomes. The aim of this retrospective study was to compare the outcomes of patients with localized ACC submitted to LA or OA in a referral center from 1995 to 2020. Among 180 consecutive patients operated on for ACC, 49 presented with localized ACC (19 LA and 30 OA). Baseline characteristics were similar between groups, except for tumor size. Kaplan-Meier estimates of 5-year overall survival were similar in both groups (p = 0.166) but 3-year disease-free survival was in favor of OA (p = 0.020). Though LA could be proposed in highly selected patients, OA should still be considered the standard approach in patients with known or suspected localized ACC.

Cancer Control, Toxicity, and Secondary Malignancy Risks of Proton Radiation Therapy for Stage I-IIB Testicular Seminoma

This study's objective was to report cancer control and toxicity outcomes after proton radiation therapy (RT) in testicular seminoma and to compare secondary malignancy (SMN) risks with photon-based treatment alternatives. Consecutive patients with stage I-IIB testicular seminoma treated with proton RT at a single institution were retrospectively analyzed. Kaplan-Meier estimates for disease-free and overall survival were computed. Toxicities were scored using Common Terminology Criteria for Adverse Events version 5.0. Photon comparison plans, including 3-dimensional conformal RT (3D-CRT) and intensity modulated RT (IMRT)/volumetric arc therapy (VMAT), were created for each patient. Dosimetric parameters and SMN risk predictions for different in-field organs-at-risk were compared between the techniques. Excess absolute SMN risks were estimated with organ equivalent dose modeling. Twenty-four patients were included (median age, 38.5 years). The majority of patients had stage II disease (IIA, 12 [50.0%]; IIB, 11 [45.8%]; IA, 1 [4.2%]). Seven (29.2%) and 17 (70.8%) patients had de novo and recurrent disease, respectively (de novo/recurrent: IA, 1/0; IIA, 4/8; IIB, 2/9). Most acute toxicities were mild (grade 1 [G1], 79.2%; G2, 12.5%) with G1 nausea being most common (70.8%). No serious events (G3-5) occurred. With a median follow-up time of 3 years (interquartile range, 2.1-3.6 years), 3-year disease-free and overall survival rates were 90.9% (95% confidence interval,68.1%-97.6%) and 100% (95% confidence interval, 100%-100%), respectively. There were no documented late toxicities in the follow-up period, including worsening serial creatinine levels suggestive of early nephrotoxicity. Proton RT had significant reductions in mean organ-at-risk doses to the kidneys, stomach, colon, liver, bladder, and body compared with both 3D-CRT and IMRT/VMAT. Proton RT had significantly lower SMN risk predictions compared with 3D-CRT and IMRT/VMAT. Cancer control and toxicity outcomes using proton RT in stage I-IIB testicular seminoma are consistent with existing photon-based RT literature. However, proton RT may be associated with significantly lower SMN risks.