Abstract
BackgroundSystematic assessment of PD-1/PD-L1 inhibitor-related neurological toxicities is important for guiding anti-PD-1 and anti-PD-L1 immunotherapy. Therefore, we conducted this meta-analysis to reveal the relationship between PD-1/PD-L1 inhibitors and neurological toxicities among cancer patients.MethodsClinical trials investigating PD-1/PD-L1 inhibitors in cancer patients were identified by a systematic search of PubMed. The random-effect model was used to synthesize individual studies. Neurological toxicities, including all-grades and grades 3–5, were taken into account for the final comprehensive meta-analysis. The Newcastle Ottawa Scale (NOS) was used to assess the quality of included trials.ResultsThirty-one clinical trials containing data of neurological toxicities were included. Compared with chemotherapy, the risk of all-grade neurological toxicities caused by PD-1/PD-L1 inhibitors was much lower in terms of peripheral neuropathy [OR = 0.07, 95%CI:(0.04, 0.13)], peripheral sensory neuropathy [OR = 0.07, 95%CI(0.04, 0.12)], dysgeusia [OR = 0.26, 95%CI:(0.19, 0.35)], paraesthesia [OR = 0.23, 95%CI:(0.14, 0.36)], and polyneuropathy [OR = 0.12, 95%CI:(0.01, 0.94)]. However, for grades 3–5, the statistically significant results were only seen in peripheral neuropathy [OR = 0.15, 95%CI:(0.07, 0.34)] and peripheral sensory neuropathy [OR = 0.13, 95%CI:(0.04, 0.40)]. No statistically significant difference regarding the risk of headache, dizziness, and Guillain–Barré syndrome was found between PD-1/PD-L1 inhibitors and chemotherapy. For PD-1/PD-L1 inhibitors plus chemotherapy, the risk trends of the above-mentioned neurological toxicities, especially grades 3–5 peripheral neuropathy [OR = 1.76, 95%CI:(1.10, 2.82)] was increased compared to chemotherapy alone.ConclusionOur comprehensive analysis showed that PD-1/PD-L1 inhibitors alone exhibited lower neurological toxicities than chemotherapy. However, the risk of headache, dizziness, and Guillain–Barré syndrome was similar between PD-1/PD-L1 and chemotherapy. For PD-1/PD-L1 inhibitors plus chemotherapy, the incidence trend of neurological toxicities would be increased, especially for peripheral neuropathy of grades 3–5.
Highlights
Cancer immunotherapies, developed to overcome the immune escape mechanisms of cancer progression and metastatic dissemination, are becoming familiar to oncologists (1), especially for programmed cell death protein 1 (PD-1) and its ligand (PD-L1) inhibitors
A total of 471 Programmed Cell Death-1 (PD-1)/Programmed Cell Death Ligand 1 (PD-L1) inhibitor-related clinical trials were identified through PubMed, while 31 related studies were collected from the former published meta-analysis (16)
When PD-1/PD-L1 inhibitors were compared with chemotherapy, the risk of peripheral neuropathy of all grades was noticeably lower [odds ratio (OR) = 0.07, 95%confidence interval (CI):(0.04, 0.13), I2 = 62%, Z = 8.48 (P < 0.00001); Figure 3A1], even for every subgroup relating to different tumor types (24–26, 30–32, 34, 38, 40, 41, 43, 44, 46)
Summary
Cancer immunotherapies, developed to overcome the immune escape mechanisms of cancer progression and metastatic dissemination, are becoming familiar to oncologists (1), especially for programmed cell death protein 1 (PD-1) and its ligand (PD-L1) inhibitors. Immunotherapies, including cytotoxic T lymphocyte antigen-4 (CTLA-4) and PD-1/ PD-L1 had changed the treatment landscape for plenty of solid tumors but conferred unique toxicity profiles owing to their unique mechanism of actions (1–3). Most of those toxic reactions had aroused sufficient attention from clinicians and researchers, and guidelines for related treatment had been developed for reference (2, 4). Systematic assessment of PD-1/PD-L1 inhibitor-related neurological toxicities is important for guiding anti-PD-1 and anti-PD-L1 immunotherapy. We conducted this meta-analysis to reveal the relationship between PD-1/PD-L1 inhibitors and neurological toxicities among cancer patients
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