Abstract
Simple SummaryImmune checkpoint inhibitors (ICIs) and radiotherapy (RT) are widely used for patients with brain metastasis (BM). To evaluate markers for treatment response and find a treatment concept which has the best outcome effects, we analyzed data of 93 patients with BM from different cancer types. Predictive markers for survival were good performance status, melanoma as cancer type, low metastasis volume, normal inflammatory blood parameters, and a stereotactic radiotherapy concept with high doses. We found that the best survival outcome can be achieved with the concurrent use of RT and ICI. Concurrent treatment was particularly beneficial in patients with low inflammatory status and more and larger metastases, and when high doses cannot be administered. In concurrently treated patients, therapeutic response was often delayed compared to sequential treatment. Specific immune responses such as pseudoprogression and abscopal effects were induced by concurrent treatment and associated with prolonged survival.While immune checkpoint inhibitors (ICIs) in combination with radiotherapy (RT) are widely used for patients with brain metastasis (BM), markers that predict treatment response for combined RT and ICI (RT-ICI) and their optimal dosing and sequence for the best immunogenic effects are still under investigation. The aim of this study was to evaluate prognostic factors for therapeutic outcome and to compare effects of concurrent and non-concurrent RT-ICI. We retrospectively analyzed data of 93 patients with 319 BMs of different cancer types who received PD-1 inhibitors and RT at the University Hospital Cologne between September/2014 and November/2020. Primary study endpoints were overall survival (OS), progression-free survival (PFS), and local control (LC). We included 66.7% melanoma, 22.8% lung, and 5.5% other cancer types with a mean follow-up time of 23.8 months. Median OS time was 12.19 months. LC at 6 months was 95.3% (concurrent) vs. 69.2% (non-concurrent; p = 0.008). Univariate Cox regression analysis detected following prognostic factors for OS: neutrophil-to-lymphocyte ratio NLR favoring <3 (low; HR 2.037 (1.184–3.506), p = 0.010), lactate dehydrogenase (LDH) favoring ≤ULN (HR 1.853 (1.059–3.241), p = 0.031), absence of neurological symptoms (HR 2.114 (1.285–3.478), p = 0.003), RT concept favoring SRS (HR 1.985 (1.112–3.543), p = 0.019), RT dose favoring ≥60 Gy (HR 0.519 (0.309–0.871), p = 0.013), and prior anti-CTLA4 treatment (HR 0.498 (0.271–0.914), p = 0.024). Independent prognostic factors for OS were concurrent RT-ICI application (HR 0.539 (0.299–0.971), p = 0.024) with a median OS of 17.61 vs. 6.83 months (non-concurrent), ECOG performance status favoring 0 (HR 7.756 (1.253–6.061), p = 0.012), cancer type favoring melanoma (HR 0.516 (0.288–0.926), p = 0.026), BM volume (PTV) favoring ≤3 cm3 (HR 1.947 (1.007–3.763), p = 0.048). Subgroups with the following factors showed significantly longer OS when being treated concurrently: RT dose <60 Gy (p = 0.014), PTV > 3 cm3 (p = 0.007), other cancer types than melanoma (p = 0.006), anti-CTLA4-naïve patients (p < 0.001), low NLR (p = 0.039), steroid intake ≤4 mg (p = 0.042). Specific immune responses, such as abscopal effects (AbEs), pseudoprogression (PsP), or immune-related adverse events (IrAEs), occurred more frequently with concurrent RT-ICI and resulted in better OS. Other toxicities, including radionecrosis, were not statistically different in both groups. The concurrent application of RT and ICI, the ECOG-PS, cancer type, and PTV had an independently prognostic impact on OS. In concurrently treated patients, treatment response (LC) was delayed and specific immune responses (AbE, PsP, IrAE) occurred more frequently with longer OS rates. Our results suggest that concurrent RT-ICI application is more beneficial than sequential treatment in patients with low pretreatment inflammatory status, more and larger BMs, and with other cancer types than melanoma.
Highlights
Advanced-stage cancer patients develop brain metastases (BMs) in 20–40% of cases.brain metastasis (BM) are most common in lung cancer, breast cancer, malignant melanoma, renal cancer, and carcinomas of the gastrointestinal tract
Besides established risk factors associated with shortened survival, such as low performance status and presence of extracranial disease, we examined other covariates potentially affecting RT-immune checkpoint inhibitors (ICIs) treatment outcome, such as different RT concepts, volume, and dosage, and factors associated with inflammation [23,24]
Disease, and treatment characteristics, treatment outcome such as overall survival (OS), progression-free survival (PFS), and local control (LC), covariates with a possible impact on treatment outcome such as Eastern Cooperative Oncology Group Performance Status (ECOG-PS), body mass index (BMI), presence of extracranial disease, which was defined as manifestation of metastatic disease outside the brain, high tumor burden, number of BMs, total mean planned target volume (PTV) of all irradiated BMs, programmed cell death ligand 1 (PD-L1) status, neutrophil-to-lymphocyte ratio (NLR), neurological symptoms, biologically effective dose (BED), RT and ICI timing, dexamethasone intake, prior systemic treatment, as well as treatment-related toxicities
Summary
Advanced-stage cancer patients develop brain metastases (BMs) in 20–40% of cases.BMs are most common in lung cancer, breast cancer, malignant melanoma, renal cancer, and carcinomas of the gastrointestinal tract. Advanced-stage cancer patients develop brain metastases (BMs) in 20–40% of cases. Current strategies for the management of BM include systemic therapy, surgery, and radiation therapy (RT), mostly applied as stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT) [1,2]. SRS is increasingly used in clinical routine since it shows comparable or even better outcomes associated with less toxicity compared to WBRT [3]. Binding of programmed cell death ligand 1 (PD-L1), expressed by cancer cells, to its receptor programmed cell death protein 1 (PD-1) on T cells sends an inhibitory signal and leads to T cell dysfunction. Targeting the PD1/PD-L1 checkpoint is an established treatment for many cancers. Another clinically used ICI targets the binding of anticytotoxic T-lymphocyte-associated protein 4 (CTLA4) to its ligands expressed by antigen-presenting cells [4]
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