Immune checkpoint inhibitors (ICI) predispose patients to immune-related adverse events (irAEs). Although hepatitis is a potentially lethal toxicity, the timing and outcomes have not been well described. In this retrospective study, patients from six international institutions were included if they were treated with ICIs and developed immune-related hepatitis. Patient and tumor characteristics, and hepatitis management and outcomes were evaluated. Of the 164 patients included, most were male (53.7%) with a median age of 63.0 years. Most patients had melanoma (83.5%) and stage IV disease (86.0%). Median follow-up was 585 days; median OS and PFS were not reached. The initial grade of hepatitis was most often grade 2 (30.5%) or 3 (45.7%) with a median time to onset of 61 days. Patients were most commonly asymptomatic (46.2%), but flu-like symptoms, including fatigue/anorexia (17.1%), nausea/emesis (14.0%), abdominal/back pain (11.6%), and arthralgias/myalgias (8.5%) occurred. Most patients received glucocorticoids (92.1%); the median time to improvement by one grade was 13.0 days, and the median time to complete resolution was 52.0 days. Second-line immunosuppression was required in 37 patients (22.6%), and steroid-dose re-escalation in 45 patients (27.4%). Five patients (3%) died of ICI-hepatitis or complications of hepatitis treatment. Ninety-one patients (58.6%) did not resume ICI; of 66 patients (40 grade 1/2, 26 grade 3/4) that were rechallenged, only 25.8% (n = 17) had recurrence. In this multi-institutional cohort, immune-related hepatitis was associated with excellent outcomes but frequently required therapy discontinuation, high-dose steroids, and second-line immunosuppression. Rechallenge was associated with a modest rate of hepatitis recurrence.

Lung cancer treatment is constantly evolving due to technological advances in the delivery of radiation therapy. Adaptive radiation therapy (ART) allows for modification of a treatment plan with the goal of improving the dose distribution to the patient due to anatomic or physiologic deviations from the initial simulation. The implementation of ART for lung cancer is widely varied with limited consensus on who to adapt, when to adapt, how to adapt, and what the actual benefits of adaptation are. ART for lung cancer presents significant challenges due to the nature of the moving target, tumor shrinkage, and complex dose accumulation because of plan adaptation. This article presents an overview of the current state of the field in ART for lung cancer, specifically, probing topics of: patient selection for the greatest benefit from adaptation, models which predict who and when to adapt plans, best timing for plan adaptation, optimized workflows for implementing ART including alternatives to re-simulation, the best radiation techniques for ART including magnetic resonance guided treatment, algorithms and quality assurance, and challenges and techniques for dose reconstruction. To date, the clinical workflow burden of ART is one of the major reasons limiting its widespread acceptance. However, the growing body of evidence demonstrates overwhelming support for reduced toxicity while improving tumor dose coverage by adapting plans mid-treatment, but this is offset by the limited knowledge about tumor control. Progress made in predictive modeling of on-treatment tumor shrinkage and toxicity, optimizing the timing of adaptation of the plan during the course of treatment, creating optimal workflows to minimize staffing burden, and utilizing deformable image registration represent ways the field is moving toward a more uniform implementation of ART.

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Renal cell carcinomas (RCC) make up about 90% of kidney cancers, of which 80% are of the clear cell subtype. About 20% of patients are already metastatic at the time of diagnosis. Initial treatment is often cytoreductive nephrectomy, but systemic therapy is required for advanced RCC. Single agent targeted therapies are moderately toxic and only somewhat effective, leading to development of immunotherapies and combination therapies. This review identifies limitations of monotherapies for metastatic renal cell carcinoma, discusses recent advances in combination therapies, and highlights therapeutic options under development. The goal behind combining various modalities of systemic therapy is to potentiate a synergistic antitumor effect. However, combining targeted therapies may cause increased toxicity. The initial attempts to create therapeutic combinations based on inhibition of the vascular endothelial growth factor or mammalian target of rapamycin pathways were largely unsuccessful in achieving a profile of increased synergy without increased toxicity. To date, five combination therapies have been approved by the U.S. Food and Drug Administration, with the most recently approved therapies being a combination of checkpoint inhibition plus targeted therapy. Several other combination therapies are under development, including some in the phase 3 stage. The new wave of combination therapies for metastatic RCC has the potential to increase response rates and improve survival outcomes while maintaining tolerable side effect profiles.