Progressive Sarcopenia Correlates with Poor Response and Outcome to Immune Checkpoint Inhibitor Therapy

Abstract

Background: Immune checkpoint inhibitors (ICIs) represent a new therapeutic standard for an increasing number of tumor entities. Nevertheless, individual response and outcome to ICI is very heterogeneous, and the identification of the ideal ICI candidate has remained one of the major issues. Sarcopenia and the progressive loss of muscle mass and strength, as well as muscular fat deposition, have been established as negative prognostic factors for a variety of diseases, but their role in the context of ICI therapy is not fully understood. Here, we have evaluated skeletal muscle composition as a novel prognostic marker in patients undergoing ICI therapy for solid malignancies. Methods: We analyzed patients with metastasized cancers receiving ICI therapy according to the recommendation of the specific tumor board. Routine CT scans before treatment initialization and during ICI therapy were used to assess the skeletal muscle index (L3SMI) as well as the mean skeletal muscle attenuation (MMA) in n = 88 patients receiving ICI therapy. Results: While baseline L3SMI and MMA values were unsuitable for predicting the individual response and outcome to ICI therapy, longitudinal changes of the L3SMI and MMA (∆L3SMI, ∆MMA) during ICI therapy turned out to be a relevant marker of therapy response and overall survival. Patients who responded to ICI therapy at three months had a significantly higher ∆L3SMI compared to non-responders (−3.20 mm2/cm vs. 1.73 mm2/cm, p = 0.002). Moreover, overall survival (OS) was significantly lower in patients who had a strongly decreasing ∆L3SMI (<−6.18 mm2/cm) or a strongly decreasing ∆MMA (<−0.4 mm2/cm) during the first three month of ICI therapy. Median OS was only 127 days in patients with a ∆L3SMI of below −6.18 mm2/cm, compared to 547 days in patients with only mildly decreasing or even increasing ∆L3SMI values (p < 0.001). Conclusion: Both progressive sarcopenia and an increasing skeletal muscle fat deposition are associated with poor response and outcome to ICI therapy, which might help to guide treatment decisions during ICI therapy.

Prognostic Impact of Sarcopenia on Clinical Outcomes in Malignancies Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

“…This analysis was performed mainly on lung cancer data and did not include other cancer types. Other studies also showed that sarcopenia was the negative impact on clinical outcomes in melanoma, urothelial carcinoma patients (18,29,30). In addition, some studies (23,28) have reported that sarcopenia had no effect on the outcome of malignancies.…”

“…Sarcopenia was defined by measuring skeletal muscle mass using CT images. The main characteristics of the included studies are summarized in Table 1 (17,18,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37).…”

“…The HR (95% CI) was 2.45 (1.09-5.53) and 3.87 (1.60-9.34) respectively (28). Another study evaluated the effect of increasing or decreasing L3SMI/median skeletal muscle attenuation and delta (Δ) L3SMI (ΔL3SMI) three months after ICI therapy on OS and reported that ΔL3SMI became a prognostic factor for OS with HR values (95% CI) of 0.929 (0.898-0.960) and 0.925 (0.890-0.961) according to univariate and univariate Coxregression analysis, respectively (30).…”

Combined Assessment of Preoperative Frailty and Sarcopenia Allows the Prediction of Overall Survival in Patients with Lung Cancer (NSCLC) and Surgically Treated Brain Metastasis

“…One of the determining aspects is the molecular profile of the tumor. Nevertheless, several studies have revealed a reduced OS in patients with sarcopenia despite treatment with immune checkpoint inhibitors [29,30]. In addition, positive PD-L1 expression was reported more frequently in patients with primary brain metastases [31].…”

Telomere Shortening in Peripheral Leukocytes Is Associated With Poor Survival in Cancer Patients Treated With Immune Checkpoint Inhibitor Therapy

“…84 patients receiving treatment with ICIs for solid malignancies at the interdisciplinary cancer outpatient clinic at the University Hospital Aachen of the RWTH Aachen University were included in this study between 2018 and 2020. The patient cohort was previously described to study novel biomarkers concerning ICI therapy ( 22 , 23 ). The study protocol was approved by the ethics committee of the University Hospital RWTH Aachen, Germany (EK 206/09) and was conducted in accordance with the ethical standards laid down in the Declaration of Helsinki.…”