Universität zu Köln

Trommer, Maike, Adams, Anne ORCID: 0000-0003-3286-1131, Celik, Eren, Fan, Jiaqi, Funken, Dominik, Herter, Jan M., Linde, Philipp, Morgenthaler, Janis, Wegen, Simone, Mauch, Cornelia, Franklin, Cindy ORCID: 0000-0001-9142-5423, Galldiks, Norbert, Werner, Jan-Michael ORCID: 0000-0001-7147-4594, Kocher, Martin ORCID: 0000-0002-5674-9227, Ruess, Daniel, Ruge, Maximilian, Meissner, Anna-Katharina, Baues, Christian ORCID: 0000-0003-1733-6064 and Marnitz, Simone (2022). Oncologic Outcome and Immune Responses of Radiotherapy with Anti-PD-1 Treatment for Brain Metastases Regarding Timing and Benefiting Subgroups. Cancers, 14 (5). BASEL: MDPI. ISSN 2072-6694

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Abstract

Simple Summary Immune 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. Abstract 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 <less than or equal to>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 cm(3) (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 cm(3) (p = 0.007), other cancer types than melanoma (p = 0.006), anti-CTLA4-naive patients (p < 0.001), low NLR (p = 0.039), steroid intake <less than or equal to>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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Trommer, Maike UNSPECIFIED UNSPECIFIED UNSPECIFIED Adams, Anne UNSPECIFIED orcid.org/0000-0003-3286-1131 UNSPECIFIED Celik, Eren UNSPECIFIED UNSPECIFIED UNSPECIFIED Fan, Jiaqi UNSPECIFIED UNSPECIFIED UNSPECIFIED Funken, Dominik UNSPECIFIED UNSPECIFIED UNSPECIFIED Herter, Jan M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Linde, Philipp UNSPECIFIED UNSPECIFIED UNSPECIFIED Morgenthaler, Janis UNSPECIFIED UNSPECIFIED UNSPECIFIED Wegen, Simone UNSPECIFIED UNSPECIFIED UNSPECIFIED Mauch, Cornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Franklin, Cindy UNSPECIFIED orcid.org/0000-0001-9142-5423 UNSPECIFIED Galldiks, Norbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Werner, Jan-Michael UNSPECIFIED orcid.org/0000-0001-7147-4594 UNSPECIFIED Kocher, Martin UNSPECIFIED orcid.org/0000-0002-5674-9227 UNSPECIFIED Ruess, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruge, Maximilian UNSPECIFIED UNSPECIFIED UNSPECIFIED Meissner, Anna-Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Baues, Christian UNSPECIFIED orcid.org/0000-0003-1733-6064 UNSPECIFIED Marnitz, Simone UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-683637
DOI:	10.3390/cancers14051240
Journal or Publication Title:	Cancers
Volume:	14
Number:	5
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language STEREOTACTIC RADIOSURGERY; RADIATION-THERAPY; IMMUNOTHERAPY; PSEUDOPROGRESSION; PEMBROLIZUMAB; INFLAMMATION; NIVOLUMAB; DIAGNOSIS; SYSTEM Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68363