Systematic Assessment of Risk of Fever in Solid Tumor Patients Treated With PD-1/PD-L1 Inhibitors: A Systematic Review and Meta-Analysis

Abstract

Purpose: Drug-induced fever is frequently reported in cancer patients treated with anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1), and stoppage of the offending agent is the management of choice. However, given the complex management of cancer patients, this needs to be carefully studied. Therefore, we conducted a meta-analysis to estimate the risk of fever associated with anti-PD-1/PD-L1 in cancer patients. Methods: From May 2010 to 2020, an electronic search was conducted through PubMed for relevant studies. All clinical trials reporting fever in cancer patients treated with PD-1/PD-L1 inhibitors were included, while other designs were excluded. A manual search was also conducted to search for relevant articles. Outcomes included the risk of pyrexia and febrile neutropenia in the overall population and based on the grade of fever (all grades vs. grades 3-5). The Newcastle-Ottawa Scale was used to assess the quality of included studies. Results: Thirty-one articles, involving 27 clinical trials and 15,867 participants, were included. The increased risk of pyrexia for all grades is only found when PD-1/PD-L1 plus cytotoxic T lymphocyte-associated protein 4 (CTLA-4) was compared to CTLA-4 [odds ratio (OR) = 2.48, 95% CI: 1.17, 5.23]. The risk of febrile neutropenia for all-grade fever was significantly lower in the PD-1/PD-L1 group compared to that of chemotherapy alone (OR = 0.02, 95% CI: 0.01, 0.05). A similar trend in the risk of febrile neutropenia was also found for grades 3-5 (OR = 0.02, 95% CI: 0.01, 0.05). Conclusion: The increased risk of pyrexia for all grades could only be found when PD-1/PD-L1 plus CTLA-4 was compared with CTLA-4. Meanwhile, compared to chemotherapy, PD-1/PD-L1 inhibitors reduced the risk of febrile neutropenia.

The Risk of Immune-Related Thyroid Dysfunction Induced by PD-1/PD-L1 Inhibitors in Cancer Patients: An Updated Systematic Review and Meta-Analysis

“…The PRISMA flow diagram was shown in ( Figure 1 ), while the bias assessment summary of all enrolled clinical trials were provided in ( Supplementary Figure 1 ). A total of 589 published studies was found by PubMed search, while 37 studies were gotten from the former published meta-analysis ( 61 – 63 ). After eligibility assessment, 5 articles were only used for the systematic review ( 13 , 20 – 23 ), while 42 articles were used for the final comprehensive analysis ( 4 – 12 , 14 – 19 , 24 – 50 ).…”

Fever of unknown origin associated with immune checkpoint inhibitors

“…Fever, caused by a wide variety of reasons, is frequently reported in cancer patients ( 37 ), and fever is one of the most prevalent adverse events after ICIs remedy ( 7 , 8 ). When immunotherapy is combined with other therapy patterns, the incidence of fever increases remarkably.…”

Risk of Rash in PD-1 or PD-L1-Related Cancer Clinical Trials: A Systematic Review and Meta-Analysis

“…On the basis of research into the mechanisms of immune escape, PD-1 or PD-L1 inhibitors have reshaped the therapy landscape for cancer by activating the immune system, while also gradually reporting plenty of treatment-related side effects [3]. Although the association between some adverse events and PD-1 or PD-L1 inhibitors has been extensively examined and documented [4][5][6][7][8][9], many toxicities remain unexplored, including skin toxicities [3].…”