Abstract
BackgroundThyroid dysfunction is common for cancer patients receiving PD-1/PD-L1 inhibitor therapies. To clarify the incidence risk of thyroid dysfunction would be important for guiding anti-PD-1 and anti-PD-L1 immunotherapy. Therefore, the updated meta-analysis was conducted to evaluate the incidence risk of thyroid dysfunction caused by PD-1/PD-L1 inhibitors.MethodsPD-1/PD-L1 inhibitor related clinical trials were collected by a systematic search of the PubMed. Some relevant studies were identified by a manual search. The incidence risk of all grades and grades 3-5 was analyzed and evaluated by random effect model. The Newcastle Ottawa Scale was used for the quality assessment of all clinical trials.ResultsForty-three clinical trials were collected. Compared with chemotherapy, the risk of hypothyroidism of all grades was significantly higher (OR=7.15, 95%CI:[4.85, 10.55], I2 = 40%, Z=9.91(P <0.00001)) in PD-1/PD-L1 group. Similar results could also be noted, when the control group was placebo or CTLA-4. When PD-1/PD-L1 was combined with other treatments for cancer patients, the risk of hypothyroidism of all grades was also significantly increased. Similar to the analysis results of hypothyroidism, PD-1/PD-L1 inhibitors played the same role in increasing the risk of hyperthyroidism and thyroiditis. Few significant analysis results was noted, when the risk of thyroid dysfunction of grades 3-5 was assessed.ConclusionWhether used alone or in combination with other anti-tumor drugs, PD-1/PD-L1 inhibitors increased the risk of thyroid dysfunction, especially for hypothyroidism. Furthermore, PD-1/PD-L1 was better than chemotherapy and CTLA-4 in increasing the risk of thyroid dysfunction.
Highlights
Programmed cell death protein 1 (PD-1) and its ligand (PD-L1) inhibitors, developed to overcome the immune escape mechanisms of cancer progression and manipulate the immune system to recognize and attack cancer cells, have been widely used for cancers (1)
In all the clinical trials included in the study, 8 tumor types are mainly involved, of which lung cancer accounts for the largest proportion (Table 1) (12–14, 16, 17, 24, 26, 27, 29, 30, 32, 33, 37, 39, 40, 42, 44–46)
We found that the risk of hypothyroidism of all grades in the Programmed Cell Death-1 (PD-1)/Programmed Cell Death Ligand 1 (PD-L1) mono-therapy group was significantly higher compared to the chemotherapy arm (Figure 2A) (4, 11, 12, 14, 15, 18, 19, 24–26, 32, 34, 37–39, 42–44)
Summary
Programmed cell death protein 1 (PD-1) and its ligand (PD-L1) inhibitors, developed to overcome the immune escape mechanisms of cancer progression and manipulate the immune system to recognize and attack cancer cells, have been widely used for cancers (1). Thyroid dysfunction was one of the common toxic side effects of PD-1/PD-L1 inhibitors and had been reported in plenty of clinical trials (4–50). It was reported that the incidence of PD-1/PD-L1 induced thyroid dysfunction was related to the clinical response and the prognosis of patients (51, 52). Clarifying the incidence risk of PD-1/PD-L1 related thyroid dysfunction would be of great significance for guiding clinical immunotherapy and judging the prognosis (51, 52). Thyroid dysfunction might appear in different forms (53), hyperthyroidism, hypothyroidism, and thyroiditis were still the most common manifestations (1), which were reported most frequently in clinical trials (4–50). Due to more and more clinical trials investigating the clinical efficacy and safety of PD-1/PD-L1 in cancer patients have been finished in recent two years (4–23), we conducted this updated metaanalysis to reassess the incidence risk of PD-1/PD-L1 induced hyperthyroidism, hypothyroidism, and thyroiditis. The updated metaanalysis was conducted to evaluate the incidence risk of thyroid dysfunction caused by PD-1/PD-L1 inhibitors
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