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Purpose: Trimodality therapy for muscle-invasive bladder cancer (MIBC) yields similar oncologic outcomes compared to radical cystectomy in appropriately selected patients; however, data regarding locally advanced MIBC (LA-MIBC) is limited. We explored our experience with LA-MIBC undergoing radiation therapy (RT). Methods: We retrospectively identified 30 patients from an institutional prospectively collated database with non-metastatic, LA-MIBC. Patients with T3-4 N0 or T2-4 N + treated from 2012 to 2022 with definitive-intent RT, who were not candidates for cystectomy were included. Kaplan-Meier analysis was used to estimate time-to-event outcomes, and multivariate analyses were conducted using Cox proportional hazards modeling. Results: 43 % had T3N0 disease, 30 % had T4N0 disease, and 27 % had node positive disease.. Neoadjuvant chemotherapy/systemic therapy was administered in 63 % of patients. Median dose and fractionation of RT was 60 Gy in 30 fractions. 23 % of patients received hypofractionated RT, 57 % received nodal RT.At a median follow-up of 20 (range, 1–75) months after RT, estimated 1- and 2-year OS was 73 % and 61 %, respectively. Estimated 1-year progression-free survival was 50 %. Local bladder failure was a component of progression in 17 % of patients, and all local bladder failure events occurred within the first 12 months following RT. Lymph node or distant metastases occurred in 23 % of patients. Estimated 1-year OS was 83 % with pure urothelial histology but only 58 % with variant histology (P = 0.001). Late grade 3 + GU and GI toxicity occurred in 7 % and 5 % of patients, respectively. Conclusions: In this cohort with LA-MIBC treated with RT, distant failures predominate, local failures are less common, and toxicity was minimal. Survival outcomes remain encouraging for RT in this challenging patient population. Further investigation is warranted to identify biomarkers for patient selection and strategies to improve distant control.

Abstract Background Small extracellular vesicle (sEV) analysis can potentially improve cancer detection and diagnostics. However, this potential has been constrained by insufficient sensitivity, dynamic range, and the need for complex labeling. Methods In this study, we demonstrate the combination of PANORAMA and fluorescence imaging for single sEV analysis. The co-acquisition of PANORAMA and fluorescence images enables label-free visualization, enumeration, size determination, and enables detection of cargo microRNAs (miRs). Results An increased sEV count is observed in human plasma samples from patients with cancer, regardless of cancer type. The cargo miR-21 provides molecular specificity within the same sEV population at the single unit level, which pinpoints the sEVs subset of cancer origin. Using cancer cells-implanted animals, cancer-specific sEVs from 20 µl of plasma can be detected before tumors were palpable. The level plateaus between 5–15 absolute sEV count (ASC) per µl with tumors ≥8 mm3. In healthy human individuals (N = 106), the levels are on average 1.5 ASC/µl (+/− 0.95) without miR-21 expression. However, for stage I–III cancer patients (N = 205), nearly all (204 out of 205) have levels exceeding 3.5 ASC/µl with an average of 12.2 ASC/µl (±9.6), and a variable proportion of miR-21 labeling among different tumor types with 100% cancer specificity. Using a threshold of 3.5 ASC/µl to test a separate sample set in a blinded fashion yields accurate classification of healthy individuals from cancer patients. Conclusions Our techniques and findings can impact the understanding of cancer biology and the development of new cancer detection and diagnostic technologies.

Background: Proton therapy (PT) has unique biologic properties with excellent clinical outcomes for the management of localized prostate cancer. Here, we aim to characterize the toxicity of PT for patients with localized prostate cancer and propose mitigation strategies using a large institutional database. Methods: We reviewed medical records of 2772 patients with localized prostate cancer treated with definitive PT between May 2006 through January 2020. Disease risk was stratified according to National Comprehensive Cancer Network guidelines as low [LR, n = 640]; favorable-intermediate [F-IR, n = 849]; unfavorable-intermediate [U-IR, n = 851]; high [HR, n = 315]; or very high [VHR, n = 117]. Descriptive statistics and Kaplan-Meier estimates assessed toxicity and freedom from biochemical relapse (FFBR). Results: Median follow-up was 7.0 years. The median dose was 78 Gy(RBE)(range: 72–79.2 Gy) in 2.0 Gy(RBE) fractions; 63 % of patients received 78 Gy(RBE) in 39 fractions, and 29 % received 76 Gy(RBE) in 38 fractions. Overall rates of late grade ≥3 GU and GI toxicity were 0.87 % and 1.01 %, respectively. Two patients developed grade 4 late GU toxicity and seven patients with grade 4 late GI toxicity. All patients experiencing severe late grade 4 toxicities were treated to 78 Gy(RBE) in 39 fractions with 80 Gy(RBE) dose to the anterior rectal wall and/or bladder neck. The 10-year FFBR rates for patients with LR to U-IR disease were compared between those treated with 76 and 78 Gy(RBE); the rates were 94.5 % (95 % confidence interval [CI] 92.4–96.0 %) and 93.2 % (95 % CI 91.3–95.7 %), respectively (log-rank p = 0.22). Conclusions: Proton therapy is associated with low rates of late grade ≥3 GU and GI toxicity. While rare, late grade 4 toxicities occurred in nine (0.3 %) patients. De-escalation to a total dose of 76 Gy(RBE) yields excellent clinical outcomes for patients with LR to U-IR disease with the potential for significant reductions in grade ≥3 late toxicity.

Objective To evaluate signal transducer and activator of transcription 3 (STAT3) inhibition we conducted a co-clinical trial testing danvatirsen, a STAT3 antisense oligonucleotide (ASO) and checkpoint inhibition in conjunction with preclinical experiments.Methods and analysis Orthotopically implanted pancreatic cancer (pancreatic adenocarcinoma (PDAC)) was treated with STAT3 ASO with immune checkpoint inhibition. Tumour infiltrating immune cell populations were characterised via flow cytometry. In vitro experiments evaluated STAT3 inhibition in pancreatic stellate cells (PSCs) and myeloid-derived suppressor cells (MDSCs).A phase II trial employing a Simon II stage design tested the clinical efficacy of danvatirsen and durvalumab in non-small cell lung cancer (NSCLC), PDAC and mismatch repair-deficient colorectal cancer (MRD CRC). The primary objective was 4-month disease control rate (DCR).Results In vivo studies identified improvement in survival of PDAC implanted mice treated with STAT3 ASO and checkpoint inhibition. Within tumour-infiltrating lymphocytes there was expansion of CD4 and PD-1+ CD8 populations with STAT3 ASO.Thirty-seven patients (29 PDAC, 7 NSCLC and 1 MRD CRC) from a single institution started treatment on trial between April 2017 and March 2020. No objective responses were observed. Four of six (66.7%, 95% CI 22.3% to 95.7%) NSCLC and 4 of 23 (17.4%, 95% CI 5% to 38.8%) PDAC patients exhibited 4-month DCR. Follow-up in vitro studies revealed an anti-inflammatory and pro-tumour effect of STAT3 ASO mediated by PSCs and MDSCs distinct from ablation of STAT3.Conclusion Although durvalumab and danvatirsen met the primary endpoint, no objective responses were observed. A rationale for the lack of objective responses is danvatirsen-induced myeloid immune suppression.Trial registration number NCT02983578.

Background Up to 20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), for which the current standard of care is radiation therapy with or without surgery. There are no prospective data on the safety of stereotactic radiosurgery (SRS) concurrent with immune checkpoint inhibitor therapy for BM. This is the safety cohort of the phase I/II investigator-initiated trial of SRS with nivolumab and ipilimumab for patients with BM from NSCLC.Patients and methods This single-institution study included patients with NSCLC with active BM amenable to SRS. Brain SRS and systemic therapy with nivolumab and ipilimumab were delivered concurrently (within 7 days). The endpoints were safety and 4-month intracranial progression-free survival (PFS).Results Thirteen patients were enrolled in the safety cohort, 10 of whom were evaluable for dose-limiting toxicities (DLTs). Median follow-up was 23 months (range 9.7–24.3 months). The median interval between systemic therapy and radiation therapy was 3 days. Only one patient had a DLT; hence, predefined stopping criteria were not met. In addition to the patient with DLT, three patients had treatment-related grade ≥3 adverse events, including elevated liver function tests, fatigue, nausea, adrenal insufficiency, and myocarditis. One patient had a confirmed influenza infection 7 months after initiation of protocol treatment (outside the DLT assessment window), leading to pneumonia and subsequent death from hemophagocytic lymphohistiocytosis. The estimated 4-month intracranial PFS rate was 70.7%.Conclusion Concurrent brain SRS with nivolumab/ipilimumab was safe for patients with active NSCLC BM. Preliminary analyses of treatment efficacy were encouraging for intracranial treatment response.

Abstract Background Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary. Results We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases. Conclusions Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity.

Purpose: To determine the clinical outcomes and toxicities of proton beam therapy (PBT) versus 3D-conformal photon radiation therapy (XRT) in patients with testicular seminoma. Materials and Methods: This observational study evaluated consecutive patients with testicular seminoma who were treated with inguinal orchiectomy and radiation therapy at a single, tertiary, high-volume center in 2008–19. Acute toxicity was scored with the Common Terminology Criteria for Adverse Events V 4.0. Organs at risk were contoured retrospectively by 2 investigators. Recurrences and secondary malignancies were based on routine follow-up imaging, either computed tomography or magnetic resonance imaging. Results: Fifty-five patients were treated with radiation therapy, 11 in the PBT-arm and 44 in the XRT-arm, with a median follow-up interval of 61 months (interquartile range [IQR]: 32–79 months). Acute treatment-related diarrhea, grade 1 to 2, was more common among XRT-treated patients (0% vs 29.5%, P =.039), and dermatitis, grade 1, was more likely among PBT-treated patients (27.3% vs 2.3%, P =.004). Dosimetrically, PBT-treated patients, relative to XRT-treated patients, had lower dose to organs at risk including the kidney, bladder, femoral head, spinal cord, bowel, pancreas, and stomach. The 5-year overall survival rate was 100% and disease-free survival rate was 96.4% for all patients. Two patients, all in the XRT-arm, had disease recurrence: 1 in the pelvis and 1 in the lung. Three patients, all in the XRT-arm, were diagnosed with a secondary malignancy: 1 in-field pancreaticoblastoma, 1 in-field colon adenocarcinoma, and a stage IV T-cell lymphoma. Conclusion: Proton beam therapy for testicular seminoma resulted in excellent clinical outcomes and was associated with lower rates of acute diarrhea but higher rates of acute dermatitis. Proton beam therapy resulted in no in-field secondary malignancies and a more favorable dosimetric profile for organs at risk relative to XRT. Reduced dose to organs at risk, such as the kidneys, may result in long-term improvement in function.

Background:: Consolidative radiotherapy (RT) has been shown to improve overall survival in oligometastatic non-small cell lung cancer (NSCLC), as demonstrated by a growing number of prospective trials. Objective:: We quantified the costs of delivery of consolidative RT for common clinical pathways associated with treating oligometastatic NSCLC, by applying time-driven activity-based costing (TDABC) methodology. Methods:: Full cycle costs were evaluated for 4 consolidative treatment regimens: (Regimen #1) 10-fraction 3D conformal radiation therapy (3D-CRT) as palliation of a distant site; (#2) 15-fraction intensity-modulated RT (IMRT) to the primary thoracic disease; (#3) 15-fraction IMRT to the primary plus 4-fraction stereotactic ablative radiotherapy (SABR) to a single oligometastatic site; and (#4) 15-fraction IMRT to the primary plus two courses of 4-fraction SABR for two oligometastatic sites. Results:: For each of the four treatment regimens, personnel represented a greater proportion of total cost when compared with equipment, totaling 61.0%, 65.9%, 66.2%, and 66.4% of the total cost of each care cycle, respectively. In total, a 10-fraction regimen of 3D-CRT to a distant site represented just 37.2% of the total cost of the most expensive course. Compared to total costs for 15-fraction IMRT alone, each additional sequential course of 4-fraction SABR imparted a cost increase of 43%. Conclusion:: This analysis uses TDABC to estimate the relative internal costs of various RT strategies associated with treating oligometastatic NSCLC. This methodology will become increasingly relevant to each organization in context of the anticipated mandate of alternative/bundled payment models for radiation oncology by the Centers for Medicare and Medicaid Services.

Purpose: Partial nephrectomy is the preferred definitive treatment for early stage kidney cancer, with tumor ablative techniques or active surveillance reserved for patients not undergoing surgery. Stereotactic body radiation therapy (SBRT) has emerged as a potential noninvasive alternative for patients with early stage kidney cancer not amenable to surgery, with early reports suggesting excellent rates of local control and limited toxicity. Methods and Materials: The national cancer database from 2004 to 2014 was queried for patients who received a diagnosis of T1N0M0 kidney cancer. Treatments were categorized as surgery (partial or total nephrectomy), tumor ablation (cryoablation or thermal ablation), SBRT (radiation therapy in 5 fractions or less to a total biological effective dose [BED10] of 72 or more), or observation. A propensity score was generated by multinomial logistic regression. A Cox proportional hazards model was fit to determine association between overall survival and treatment group with propensity score adjustments for patient, demographic, and treatment characteristics. Results: A total of 165,298 received surgery, 17,196 underwent tumor ablation, 104 underwent SBRT, and 18,241 were observed. Median follow-up was 51 months. On multivariable analysis, surgery, tumor ablation, and SBRT were associated with a decreased risk of death compared with observation, with hazard ratios of 0.25 (95% confidence interval, 0.24-0.26, P < .001), 0.36 (0.35-0.38, P < .001), and 0.56 (0.39-0.79, P < .001), respectively. When stratifying by BED10 and compared with observation, hazard ratio for risk of death for patients treated with SBRT to a BED10 ≥100 (n = 62) and a BED10

ObjectivesThis study sought to evaluate advanced psychometric properties of the 15-item Economic Strain and Resilience in Cancer (ENRICh) measure of financial toxicity for cancer patients.MethodsWe surveyed 515 cancer patients in the greater Houston metropolitan area using ENRICh from March 2019 to March 2020. We conducted a series of factor analyses alongside parametric and non-parametric item response theory (IRT) assessments using Mokken analysis and the graded response model (GRM). We utilized parameters derived from the GRM to run a simulated computerized adaptive test (CAT) assessment.ResultsAmong participants, mean age was 58.49 years and 278 (54%) were female. The initial round factor analysis results suggested a one-factor scale structure. Negligible levels of differential item functioning (DIF) were evident between eight items. Three items were removed due to local interdependence (Q3>+0.4). The original 11-point numerical rating scale did not function well, and a new 3-point scoring system was implemented. The final 12-item ENRICh had acceptable fit to the GRM (pConclusionThese CAT and 4-item versions provide options for quick screening in clinical practice and low-burden assessment in research.

Abstract Background Preclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor’s response to immunotherapy, when combined with high-dose radiation to another tumor. The aim of this study was to evaluate tumor responses to this combination in a clinical setting. Methods A post-hoc analysis of 3 ongoing immunoradiation trials was performed. Twenty-six (of 155) patients received low-dose radiation (1–20 Gy total), either as scatter from high-dose radiation or from intentional treatment of a second isocenter with low-dose radiation, were evaluated for response. The low-dose lesions were compared to lesions that received no radiation (

Adaptive MR-guided radiotherapy (MRgRT) is a new treatment paradigm and its role as a non-invasive treatment option for renal cell carcinoma is evolving. The early clinical experience to date shows that real-time plan adaptation based on the daily MRI anatomy can lead to improved target coverage and normal tissue sparing. Continued technological innovations will further mitigate the challenges of organ motion and enable more advanced treatment adaptation, and potentially lead to enhanced oncologic outcomes and preservation of renal function. Future applications look promising to make a positive clinical impact and further the personalization of radiotherapy in the management of renal cell carcinoma.

Background In this phase I/II trial, we evaluated the safety and effectiveness of pembrolizumab, with or without concurrent radiotherapy (RT), for lung and liver lesions from metastatic non-small cell lung cancer (mNSCLC).Methods Patients with lung or liver lesions amenable to RT plus at least one additional non-contiguous lesion were included regardless of programmed death-ligand 1 (PD-L1) status. Pembrolizumab was given at 200 mg every 3 weeks for up to 32 cycles with or without concurrent RT. Metastatic lesions were treated with stereotactic body RT (SBRT; 50 Gy in 4 fractions) if clinically feasible or with traditionally fractionated RT (45 Gy in 15 fractions) if not. The primary end point was the best out-of-field lesion response, and a key secondary end point was progression-free survival (PFS).Results The median follow-up time was 20.4 months. One hundred patients (20 phase I, 80 phase II) were evaluable for toxicity, and 72 phase II patients were evaluable for treatment response. No patients in the phase I group experienced grade 4–5 events; in the phase II group, two had grade 4 events and nine had grade 3 events. The ORR in the combined-modality cohort (irrespective of RT schema) was 22%, vs 25% in the pembrolizumab group (irrespective of receipt of salvage RT) (p=0.99). In the concurrent pembrolizumab+RT groups, the out-of-field ORRs were 38% in the pembrolizumab+SBRT group and 10% in the pembrolizumab+traditional RT group. When examining the pembrolizumab-alone patients, the out-of-field ORRs were 33% in those designated to receive salvage SBRT (if required) and 17% for salvage traditional RT. In all patients, the median PFS for pembrolizumab alone was 5.1 months (95% CI 3.4 to 12.7 months), and pembrolizumab/RT (regardless of schema) was 9.1 months (95% CI 3.6 to 18.4 months) (p=0.52). An exploratory analysis revealed that for patients with low PD-L1 expression, the median PFS was 4.6 vs 20.8 months for pembrolizumab with and without RT, respectively (p=0.004).Conclusions Concurrent immunoradiotherapy for mNSCLC is safe, although larger trials are required to address which patients benefit most from RT.Trial registration number NCT02444741.

Purpose: Although immunotherapy is a rapidly emerging modality for cancer care, there have been multiple reports of fatal toxicities. There have also been cases of treatment-related deaths with combined non-immunotherapeutic biologic compounds with radiation therapy. Thus, provision of summative information appraising the safety of combinatorial immunotherapy and radiation therapy (iRT) is imperative. Because this has not been well characterized, this review summarizes the available evidence to date. Methods and materials: Owing to the heterogeneity and relatively low quantity of published reports, this review was conducted in a narrative rather than systematic format. Results: The results of combined iRT, both concurrent and sequential, are discussed for oncologic therapy of the brain, lung, liver, and prostate. Most evidence is from small samples and shorter follow-up but does consist of multiple prospective publications. Most data exist for ipilimumab, with programmed cell death -1 inhibitors emerging in more recent years. With 2 large phase 3 trials as exceptions, there were no instances of iRT-related deaths across all discussed studies. Altogether, grade 3 to 4 toxicities were relatively low in frequency; of the studies that compared iRT with an “immunotherapy only” or “RT only” cohort, none documented a clear increase in high-grade adverse events with combined-modality management. Conclusions: Despite the low quantity of data, combined iRT offers encouraging safety profiles. There is no evidence that iRT produces an overt increase in high-grade toxicities. Further data, especially on concurrent iRT, are anticipated from numerous iRT trials that are currently ongoing worldwide.

Purpose: Radiomics has shown great promise to use quantifiable imaging characteristics to predict the behavior and prognosis of neoplasms. This is the first study to evaluate whether radiomic texture analysis can predict outcomes in gastroesophageal junction adenocarcinoma (GEJAC) treated with neoadjuvant chemoradiotherapy (CRT). Materials and Methods: Pretreatment contrast-enhanced CT images of 146 patients with stage II-III GEJAC were reviewed (2009–2011), and randomly split into training and validation groups at a 1:1 ratio stratified with baseline clinical characteristics. Whole-tumor texture was assessed using quantitative image features based on intensity, shape, and gray-level co-occurrence matrix. The relevant pretreatment texture features, in addition to the significant baseline clinical features to predict survival, were identified using multivariate Cox proportional hazard regression model with stepwise variable selection in the training sample and verified in the validation sample, to facilitate the proposal of a multi-point index for standard patient pre-treatment risk classification. Results: Of the factors identified in the training cohort independently associated with OS, only shape compactness (p = 0.04) and pathologic grade differentiation (PDG) (p = 0.02) were confirmed in the validation sample. Using both parameters, we created a 3-point risk classification index: low-risk (well-moderate PDG and high compactness), medium-risk (poor PDG or low compactness), and high-risk (poor PDG and low compactness). The risk index showed a strong negative association with postoperative pathologic complete response (pCR) (p = 0.04). Median OS for the high-, medium-, and low-risk groups were 23, 51, and ≥72 months, respectively (p