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Background: Characterize indications for pediatric palliative-intent proton radiation therapy (PIPRT). Procedure: We retrospectively reviewed patients ≤21 years who received PIPRT. We defined PIPRT as radiotherapy (RT) aimed to improve cancer related symptoms/provide durable local control in the non-curative setting. Mixed proton/photon plans were included. Adjacent reirradiation (reRT) was defined as a reRT volume within the incidental dose cloud of a prior RT target, whereas direct reRT was defined as in-field overlap with prior RT target. Acute toxicity during RT until first inspection visit was graded according to the Common Terminology Criteria for Adverse Events. The Kaplan-Meier method, measured from last PIPRT fraction, was used to assess progression free survival (PFS) and overall survival (OS). Results: 18 patients underwent PIPRT between 2014-2020. Median age at treatment start was 10 years (2-21). Median follow up was 8.2 months (0-48). Treatment sites included: brain/spine (10), abdomen/pelvis (3), thorax (3) and head/neck (2). Indications for palliation included: durable tumor control (18), neurologic symptoms (4), pain (3), airway compromise (2), and great vessel compression (1). Indications for protons included: reRT (15) (4 adjacent, 11 direct), craniospinal irradiation (4), reduction of dose to normal tissues (3). 16 experienced grade (G) 1-2 toxicity; 2 G3. There were no reports of radionecrosis. Median PFS was 5.3 months (95% CI 2.7-16.3). Median OS was 8.3 months (95% CI 5.5-26.3). Conclusions: The most common indication for PIPRT was reRT to provide durable tumor control. PIPRT appears to be safe, with no cases of high grade toxicity.

PDF file - 136K, Profile of studies used in this meta-analysis. Of the 51 original articles included in this report, 49 are shown here: two were excluded from this table as they did not contribute to any of the main analyses (case-only). Contribution to aims 1-3 are indicated by √ in initiation of carcinogenesis, progression of disease, and overall risk of cervical cancer, respectively.

PDF file - 108K, Supplementary Figure 1. Funnel plot for included studies that evaluated overall risk. The included studies were summarized in Supplementary Table 1. Supplementary Figure 2. Forest plot with OR for risk of cervical cancer compared to normal controls. OR and heterogeneity measures are shown for each subset as a subtotal A) HPV positive subset; B) HPV negative subset and for the pooled analysis as a total. Weights of individual studies are represented by black boxes. Diamonds represent weighted OR with 95% confidence limits. Recessive model shown.

Treatment efficacy with chimeric antigen receptor (CAR) T cell therapy in glioblastoma (GBM) is undermined by an immunosuppressive tumor microenvironment (TME). We previously showed that CAR T cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces anti-tumor activity against recurrent GBM and causes upregulation of programmed death-ligand 1 (PD-L1) in the TME. Here, we conducted a phase I trial to study the impact of CART-EGFRvIII cells administered concomitantly with the PD-1 inhibitor pembrolizumab in patients (n = 7) with newly diagnosed, EGFRvIII + GBM. Treatment was well tolerated without incidence of dose-limiting toxicity. However, no signal of efficacy was detected with a median progression-free survival of 5.2 months (90% CI, 2.9–6.0 months) and median overall survival of 11.8 months (90% CI, 9.2–14.2 months). In addition, PD-1 expression in the CART-EGFRvIII infusion product did not correlate with outcomes, and peripheral CAR T cell engraftment was relatively short-lived. Together, these findings show the safety of combining CAR T cells and PD-1 inhibition in GBM but given the lack of efficacy, also indicate a need to consider alternative combinatorial strategies. ClinicalTrials.gov registration: NCT03726515.

Managing pediatric patients requiring daily general anesthesia (GA) for radiation therapy (RT) in the setting of COVID-19 is complex, owing to the aerosolizing nature of GA procedures, the risk of cardiopulmonary complications for infected patients, and the treatment of immunocompromised oncology patients in a busy, densely populated radiation oncology clinic.We developed an institutional protocol to define procedures for COVID-19 testing and protection of patients, caregivers, and staff, hypothesizing that this protocol would allow patients requiring GA to be safely treated, minimizing COVID-19 transmission risk to both patients and staff, and at the same time maintaining pre-COVID-19 patient volumes. All patients underwent COVID-19 testing before their first treatment and thrice weekly during treatment. For patients who tested positive for COVID-19, RT was delivered in the last end-of-day treatment appointment. A negative pressure room was used for GA induction and recovery, and separate physician/nurse teams were designated for in-room versus out-of-room patient management.Seventy-eight pediatric patients received RT under GA, versus 69 over the same prior year timeframe, and 2 patients received 2 courses of RT under GA, for a total of 80 courses. The mean age was 4.9 years (range, 0.5-19.0 years) and 41 of 78 (52.6%) were male. Two patients (2.6%) received 2 courses of RT under GA, establishing a total of 80 courses. The mean number of treatment fractions was 22.2 (range, 1-40). Two of 78 patients (2.6%) tested positive for COVID-19; both were asymptomatic. Both patients completed treatment as prescribed. Neither patient developed cardiopulmonary symptoms complicating anesthesia, and neither patient experienced grade 3+ acute radiation toxicity.With careful multidisciplinary planning to mitigate COVID-19 risk, pediatric RT with GA was carried out for a large patient volume without widespread infection and without increased toxic effects from either GA or RT.

BACKGROUND We evaluated the combination of retifanlimab, INCAGN01876, and FSRT in patients with recurrent GBM. METHODS Phase II, single-center, 2 cohort study (A: single-arm non-surgical cohort; B, two-arm neoadjuvant/surgical cohort). Cohort A patients received pre-FSRT one-time doses of retifanlimab (500mg) and INCAGN01876 (300mg), FSRT (8 Gy x 3 fractions), and post-FSRT 28-day treatment cycles (retifanlimab, day 1; INCAGN01876, days 1, 15). Cohort B patients received pre-surgery doses of retifanlimab + INCAGN01876; subsequently, patients either went directly to resection (Sub-Arm 1) or to FSRT followed by resection (Sub-Arm 2). All patients resumed immunotherapy post-operatively. Primary endpoint: ORR in Cohort A. Data cut-off for this analysis was June 30, 2022. RESULTS Thirty-two evaluable patients: Cohort A, n=16; Cohort B, n=16 (Sub-Arm 1, n=8, Sub-Arm 2, n=8). Median follow-up time: Cohort A, 13.6 months; Cohort B, 8.8 months. Forty-four percent women, median age 64 (IQR, 55–65), 56% MGMT unmethylated. Most common grade 3/4 treatment-related AEs included cerebral edema (25%), lymphopenia (16%), and cognitive disturbance (13%). Efficacy in Cohort A: no objective responses observed, best response of stable disease achieved in 9/16 patients (56%), median PFS 3.9 months (95% CI 2.1 – 6.2 months), median OS 9.8 months (95% CI 8.3 months – not reached [NR]). Efficacy in Cohort B: median PFS NR, median OS 15.1 months (95% CI 8.5 months – NR). Median PFS and OS are longer in Cohort B Sub-Arm 2 compared to Cohort B Sub-Arm 1 (PFS, NR vs. 2.2 months, p = 0.009; OS, NR vs. 8.5 months, p=0.026). Results of tissue and blood-based immune correlative analyses will be presented. CONCLUSIONS The combination of retifanlimab, INCAGN01876, and FSRT is generally well-tolerated in patients with recurrent GBM when administered with or without surgical resection. Survival outcomes in the neoadjuvant cohort are encouraging, largely driven by patients that received neoadjuvant FSRT.

e20019 Background: The anti-CTLA4 antibody, ipi, improves survival in metastatic melanoma. Combined radiotherapy (RT) and ipi may increase immune response to improve outcomes but also increase toxi...

BACKGROUND: Ipilumumab (Ipi), an antibody that enhances T-cell activation, has been shown to improve survival in patients with metastatic melanoma. Ipilumumab may have synergistic effects with radiotherapy but this may result in increased toxicity. This study investigated the incidence of acute radiation effect (ARE) in patients with melanoma brain metastases treated with Ipi and radiosurgery (SRS) or whole brain radiotherapy (WBRT). METHODOLOGY: This retrospective study included metastatic melanoma patients treated at our institution from 2008-2013 who received SRS or WBRT for brain metastases within 4 months of Ipi treatment. We evaluated the incidence, timing and factors associated with acute radiation effect (ARE). RESULTS: From 159 patients treated with Ipi, 22 patients also received brain RT within 4 months of treatment. Three patients were excluded for lack of follow-up brain imaging, thus 19 were analysed: 14 males and 5 females, with median age 58 years (range 24-82). Ten were treated with SRS, 7 with WBRT, and 2 with SRS plus WBRT. Median dose for SRS was 21 Gy (range: 15-24 Gy). Five of 13 patients treated with SRS (38%) experienced symptomatic edema requiring steroids within 1 month of starting Ipi, and within 4 months of RT. One patient had a haemorrhage and 1 required surgical resection, which demonstrated viable disease. Therefore 3 patients (23%) treated with SRS developed isolated ARE. These metastases had volumes less than 4.2 cm3 and were treated within 4 months of Ipi to a median dose of 19.5 Gy (range 15-21 Gy). No patients with WBRT alone developed ARE. CONCLUSIONS: Following SRS for brain mets and Ipi, ARE was seen in 23% of patients within 4 months of starting Ipi treatment. This is greater than the commonly reported 10% risk of ARE after SRS alone for brain metastasis. No increased toxicity was seen with WBRT and Ipi.