Background Immune checkpoint inhibitors (ICIs) improve survival outcomes in metastatic melanoma and non-small cell lung cancer (NSCLC). Preclinical evidence suggests that overexpression of cyclo-oxygenase-2 (COX2) in tumors facilitates immune evasion through prostaglandin E2 production and that COX inhibition synergizes with ICIs to promote antitumor T-cell activation. This study investigates whether concurrent COX inhibitor (COXi) use during ICI treatment compared with ICI alone is associated with improved time-to-progression (TTP), objective response rate (ORR) and overall survival (OS) in patients with metastatic melanoma and NSCLC. Methods We retrospectively reviewed 90 metastatic melanoma and 37 metastatic NSCLC patients, treated with ICI between 2011 and 2019. Differences in TTP and OS by ICI+COXi versus ICI alone were compared using Kaplan-Meier and Cox regression. Interaction between ICI+COXi versus ICI alone and pretreatment neutrophil–lymphocyte ratio (NLR) was examined. Independent radiology review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was performed. Results For patients with melanoma, median TTP was significantly prolonged in ICI+COXi versus ICI alone (245 vs 100.5 days, p=0.002). On multivariate analysis, ICI+COXi associated with increased TTP (HR 0.36, 95% CI 0.2 to 0.66, p=0.001), adjusted for age, pretreatment NLR, and gender. For NSCLC patients, ICI+COXi also associated with increased TTP compared with ICI alone on multivariate analysis (HR 0.45; 95% CI 0.21 to 0.97; p=0.042) adjusted for age. ORR at 6 months was significantly higher in patients who received ICI+COXi compared with ICI alone in both melanoma (58.6% vs 19.2%, p=0.0005) and NSCLC (73.7% vs 33.3%, p=0.036) cohorts. In the melanoma cohort, high pretreatment NLR (>5) associated with decreased TTP (HR 3.21, 95% CI 1.64 to 6.3; p=0.0007); however, ICI+COXi significantly associated with increased TTP in high NLR (>5) patients (HR 0.08, 95% CI 0.03 to 0.25), but not in low NLR (≤5) patients (HR 0.65, 95% CI 0.32 to 1.32). Similar outcomes were found in an adjusted melanoma cohort after RECIST review. Conclusions Our study suggests that COXi use concurrently with ICI significantly associated with longer TTP and improved ORR at 6 months in patients with metastatic melanoma and NSCLC compared with ICI alone. Furthermore, COXi use appears to reverse the negative prognostic effect of a high NLR by prolonging TTP in patients with melanoma.

Recent development in radiation biology has revealed potent immunogenic properties of radiotherapy in cancer treatments. However, antitumor immune effects of radiotherapy are limited by the concomitant induction of radiation-dependent immunosuppressive effects. In the growing era of immunotherapy, combining radiotherapy with immunomodulating agents has demonstrated enhancement of radiation-induced antitumor immune activation that correlated with improved treatment outcomes. Yet, how to optimally deliver combination therapy regarding dose-fractionation and timing of radiotherapy is largely unknown. Future prospective testing to fine-tune this promising combination of radiotherapy and immunotherapy is warranted.

Objective Metastatic melanoma patients often receive palliative radiotherapy (RI') and immunotherapy (IT). However, the immunological interplay between RT dose-fractionation and IT is uncertain, and the optimal treatment strategy using RT and IT in metastatic melanoma remains unclear. Our main objective was to examine the effect of RT dose-fractionation on overall survival (OS). Methods Using the National Cancer Database (NCDB), we classified metastatic melanoma patients who received palliative RT into two dose-fractionation groups - conventionally fractionated RT (CFRT; = 5 Gy/fraction) - with or without IT. Survival analysis was performed using the Cox regression model, Kaplan-Meier method, and propensity-score matching (PSM). Results A total of 5,281 metastatic melanoma patients were included, with a median follow-up of 5.9 months. The three-year OS was highest in patients who received HFRT+IT [37.3% (95% CI: 31.1-43.5)] compared to those who received HFRT alone [19.0% (95% CI: 16.2-21.9)], CFRT+IT [17.6 (95%CI: 13.9-21.6)], or CFRT alone [8.6% (95%CI: 7.6-9.7); p<0.0001]. The magnitude of OS benefit with the use of IT was greater in those who received HFRT (18.3%) compared with those who received CFRT (9.0%) (p<0.0001). The addition of IT to HFRT, compared to CFRT, was associated with greater OS benefit in patients treated with RI' to the brain and soft tissue/visceral (STV) sites. On PSM analysis, HFRT+IT was associated with improved three-year OS compared to other treatments. Conclusion Metastatic melanoma patients who received HFRT+IT was associated with the greatest OS benefit. Our findings warrant further prospective evaluation as to whether higher RI' dose-perfraction improves clinical outcomes in metastatic melanoma patients receiving IT.

Stereotactic ablative radiotherapy (SABR) has challenged the conventional wisdom surrounding the radioresistance of renal cell carcinoma (RCC). In the past decade, there has been a significant accumulation of clinical data to support the safety and efficacy of SABR in RCC. Herein, we review the use of SABR across the spectrum of RCC. We performed an online search of the Pubmed database from January 1990 through April 2023. Studies of SABR/stereotactic radiosurgery targeting primary, extracranial, and intracranial metastatic RCC were included. For SABR in non-metastatic RCC, this includes its use in small renal masses, larger renal masses, and inferior vena cava tumor thrombi. In the metastatic setting, SABR can be used at diagnosis, for oligometastatic and oligoprogressive disease, and for symptomatic reasons. Notably, SABR can be used for both the primary renal tumor and metastasis-directed therapy. Management of RCC is evolving rapidly, and the role that SABR will have in this landscape is being assessed in a number of ongoing prospective clinical trials. The objective of this narrative review is to summarize the evidence corroborating the use of SABR in RCC.

Globally, prostate cancer is one of the most common malignancies affecting men. With the advent of advanced molecular imaging, an increasing number of men are found to have oligometastatic disease (OD) either at primary diagnosis or at the time of biochemical failure. No strict definition exists for OD, with historical and ongoing studies utilizing diverse criteria. There is mounting evidence from many different malignancies that patients with OD have improved outcomes compared to their widely metastatic counterparts. As such, treatment intensification of those with OD or oligoprogressive disease has become an area of intense interest and study. This article will review the biology, evidence and controversy behind the treatment of de novo oligometastatic, oligorecurrent and oligoprogressive prostate cancer.