Renal cell carcinoma (RCC) has long been termed a radioresistant histology owing to older data demonstrating a lack of benefit with conventional fractionated radiation.1, 2 More modern series have demonstrated that high-dose regimens delivered using stereotactic body radiation therapy (SBRT) offer impressive tumor control.3, 4 Preservation of normal kidney function is a priority when using radiation therapy (RT). Investigators have previously noted decreased renal function after SBRT, especially in patients with pre-existing renal disease.5, 6 The effectiveness of SBRT correlates with accurate tumor delineation and avoidance of high-dose radiation to normal tissue. Furthermore, treatment planning must compensate for respiratory motion of renal tumors. We report a case illustrating a patient with metastatic RCC who responded on systemic therapy with nivolumab and underwent SBRT to the primary renal mass for a cytoreductive effect. This SBRT regimen was delivered using a magnetic resonance (MR) imaging (MRI)-guided RT system that allows for MR-based simulation imaging, real-time tumor tracking, and respiratory gating. We further highlight the implications of this novel system in treatment planning, treatment delivery, and potential outcomes.

Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors, have immunomodulatory properties and have offered promising results when combined with anti-PD-1 agents. We conducted a phase 2, multicenter, single-arm trial of pembrolizumab and cabozantinib in patients with RMHNSCC who had Response Evaluation Criteria in Solid Tumors v.1.1 measurable disease and no contraindications to either agent. We assessed the primary end points of tolerability and overall response rate to the combination with secondary end points of progression-free survival and overall survival and performed correlative studies with PDL-1 and combined positive score, CD8+ T cell infiltration and tumor mutational burden. A total of 50 patients were screened and 36 were enrolled with 33 evaluable for response. The primary end point was met, with 17 out of 33 patients having a partial response (52%) and 13 (39%) stable disease with an overall clinical benefit rate of 91%. Median and 1-year overall survival were 22.3 months (95% confidence interval (CI) = 11.7–32.9) and 68.4% (95% CI = 45.1%–83.5%), respectively. Median and 1-year progression-free survival were 14.6 months (95% CI = 8.2–19.6) and 54% (95% CI = 31.5%–72%), respectively. Grade 3 or higher treatment-related adverse events included increased aspartate aminotransferase (n = 2, 5.6%). In 16 patients (44.4%), the dose of cabozantinib was reduced to 20 mg daily. The overall response rate correlated positively with baseline CD8+ T cell infiltration. There was no observed correlation between tumor mutational burden and clinical outcome. Pembrolizumab and cabozantinib were well tolerated and showed promising clinical activity in patients with RMHNSCC. Further investigation of similar combinations are needed in RMHNSCC. The trial is registered at ClinicalTrials.gov under registration no. NCT03468218.

We conducted a prospective pilot study evaluating the feasibility of same day MRI-only simulation and treatment with MRI-guided adaptive palliative radiotherapy (MAP-RT) for urgent palliative indications (NCT#03824366). All (16/16) patients were able to complete 99% of their first on-table attempted fractions, and no grades 3–5 toxicities occurred.

PURPOSE/OBJECTIVE(S): Low-dose radiotherapy (LD-RT) is a well-established treatment for multiple human inflammatory conditions. Whole-lung LD-RT may be effective in COVID-19-related pneumonia. MATERIALS/METHODS: Patients hospitalized with COVID-19-related pneumonia receiving supportive care, glucocorticosteroids, and/or remdesivir were administered LD-RT treatment of 0.5 or 1.5 Gy to the bilateral lungs on a prospective, combined phase I/II, multi-site, single-institution trial. Patients were followed for 28 days or until discharge and compared to controls blindly matched by age, comorbidity, duration of symptoms, and disease severity. Eligible patients were confirmed by SARS-CoV-2 positive PCR, unable to wean from oxygen at enrollment, and had radiographic consolidations. Patients were enrolled into 5 cohorts stratified by treatment variables and severity of illness: LD-RT alone vs. LD-RT with concurrent drug therapies, non-intubated vs. intubated status, and low (1.5 Gy) vs. lower (0.5 Gy) radiation dose. Qualitative aims were to establish safety and explore efficacy. Quantitative endpoints were continuous, categorical, and time-to-event, and included clinical recovery, intubation, radiographic changes, and biomarker responses. Intubation endpoints are reported for all cohorts using the log-rank test and Kaplan-Meier method. RESULTS: Outcomes of 80 patients were available for analysis at study closure. In total, 40 of 70 planned patients (57% trial enrollment) received whole-lung LD-RT between April 24 and December 7, 2020 and were compared to 40 matched controls. Cohorts 1&2: Ten non-intubated patients received 1.5 Gy without concurrent COVID-directed drug therapies (10 of 10 planned, 100% cohort enrollment) and were compared to matched controls. Intubation rates were 40% in controls compared to 10% following LD-RT (P = 0.11). Cohort 3: One intubated patient received 1.5 Gy (1 of 20 planned, 5% cohort enrollment). Cohort 4: Twenty separate non-intubated patients received 1.5 Gy with concurrent dexamethasone/remdesivir (20 of 20 planned, 100% cohort enrollment) and were compared to matched controls. Intubation rates were 32% in controls compared to 14% following LD-RT (P = 0.09). Cohort 5: Nine patients received 0.5 Gy with concurrent drug therapies (9 of 20 planned, 45% cohort enrollment) and were compared to matched controls. Zero controls required intubation compared to 11% following LD-RT (P = 0.32). Among all non-intubated patients and matched controls combined (n = 78), mechanical ventilation was required in 28% of controls compared to 12% following LD-RT (reduced 57%, P = 0.05). The trial was prematurely closed due to observed reproducibility of efficacy. A randomized trial is now ongoing. CONCLUSION: In the first, prospective, phase I/II trial of radiotherapy for COVID-19-related pneumonia, a single treatment of whole-lung LD-RT reduced intubation rates by 57% compared to controls in patients receiving supportive care with or without drug therapies (P = 0.05).

Background: Low-dose radiotherapy (LD-RT) has produced anti-inflammatory effects in both animal models and early human trials of COVID-19-related pneumonia. The role of whole-lung LD-RT within existing treatment paradigms merits further study. Methods: A phase II prospective trial studied the addition of LD-RT to standard drug treatments. Hospitalized and oxygen-dependent patients receiving dexamethasone and/or remdesevir were treated with 1.5 Gy whole-lung LD-RT and compared to a blindly-matched contemporaneous control cohort. Results: Of 40 patients evaluated, 20 received drug therapy combined with whole-lung LD-RT and 20 without LD-RT. Intubation rates were 14% with LD-RT compared to 32% without (p = 0.09). Intubation-free survival was 77% vs. 68% (p = 0.17). Biomarkers of inflammation (C-reactive protein, p = 0.02) and cardiac injury (creatine kinase, p < 0.01) declined following LD-RT compared to controls. Mean time febrile was 1.4 vs 3.3 days, respectively (p = 0.14). Significant differences in clinical recovery (7.5 vs. 7 days, p = 0.37) and radiographic improvement (p = 0.72) were not detected. On subset analysis, CRP decline following LD-RT was predictive of recovery without intubation compared to controls (0% vs. 31%, p = 0.04), freedom from prolonged hospitalizations (21+ days) (0% vs. 31%, p = 0.04), and decline in oxygenation burden (56% reduction, p = 0.06). CRP decline following 1st drug therapy was not similarly predictive of outcome in controls (p = 0.36). Conclusions: Adding LD-RT to standard drug treatments reduced biomarkers of inflammation and cardiac injury in COVID-19 patients and may have reduced intubation. Durable CRP decline following LD-RT predicted especially favorable recovery, freedom from intubation, reduction in prolonged hospitalization, and reduced oxygenation burden. A confirmatory randomized trial is now ongoing. Clinical Trial Registration: NCT04366791.

Background: Optimal management for recurrent IDH-mutant glioma after radiation therapy (RT) is not well-defined. This study assesses practice patterns for managing recurrent IDH-mutant astrocytoma (Astro) and 1p/19q codeleted oligodendroglioma (Oligo) after RT and surveys their clinical outcomes after different salvage approaches. Methods: Ninety-four recurrent Astro or Oligo patients after RT who received salvage systemic therapy (SST) between 2001 and 2019 at a tertiary cancer center were retrospectively analyzed. SST was defined as either alkylating chemotherapy (AC) or nonalkylating therapy (non-AC). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method from the start of SST. Multivariable analysis (MVA) was conducted using Cox regression analysis. Results: Recurrent Oligo (n = 35) had significantly higher PFS (median: 3.1 vs 0.8 years, respectively, P = .002) and OS (median: 6.3 vs 1.5 years, respectively, P < .001) than Astro (n = 59). Overall, 90% of recurrences were local. Eight-three percent received AC as the first-line SST; 50% received salvage surgery before SST; approximately 50% with local failure >2 years after prior RT received reirradiation. On MVA, non-AC was associated with worse OS for both Oligo and Astro; salvage surgery was associated with improved PFS and OS for Astro; early reirradiation was associated with improved PFS for Astro. Conclusions: Recurrent radiation-relapsed IDH-mutant gliomas represent a heterogeneous group with variable treatment approaches. Surgery, AC, and reirradiation remain the mainstay of salvage options for retreatment.